Widespread Abnormalities Research Articles

Impaired retinal micro-vascular function in patients with a systemic sclerosis

Abstract Background Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by widespread and progressive multi-organ fibrosis and vascular abnormalities. Endothelial dysfunction is an early manifestation of SSc and an important contributor to the progression and prognosis of the disease. Dynamic retinal vascular analysis (DVA) is a new method for non-invasive and precise determination of microvascular function. The primary aim was to assess micro- and macro-vascular function in patients with SSc. Methods In this study, vascular function was measured non-invasively with flicker-light induced vasodilation of retinal arterioles (FIDart) and branchial arterial flow-mediated vasodilation (FMD). Patients with SSc were prospectively enrolled in the study (n = 40; mean ± SD age 56±11 years, females 73 %) and compared with age- and sex-matched HC (n = 40; mean age 56±15 years, females 73%). Results Retinal microvascular function was significantly impaired in patients with SSc compared to matched HC (2.3±2.0% versus 3.1±1.9% respectively, p=0.04, figure 1). There was a trend for lower FMD in patients with SSc in comparison to HC (5.0± 3.2% versus 6.2±3.2% respectively, p=0.07). Conclusion Patients with SSc have severe impairment of retinal vascular function compared to matched HC. Thus, microvascular dysfunction in these patients is of systemic nature and retinal vessel analysis may serve as an important marker for SSc disease, severity and prognosis. These results set the stage for further studies on retinal function in SSc patients.Figure 1

Assessing changes in brain structure in new-onset children with acute lymphoblastic leukemia.

Brain structure injury was presented in acute lymphoblastic leukemia (ALL) after treatment; however, its alterations in new-onset stage are still unclear. We aim to explore white matter (WM) and grey matter (GM) alterations using surface-based morphometry (SBM) and tract-based spatial statistics (TBSS) in new-onset pediatric ALL. Thirty-five ALL and 33 typically developing (TD) children were prospectively recruited and underwent three-dimensional T1-weighted and diffusion tensor (DTI) imaging. DTI metrics, cortical GM features, anddeep GM nuclei volume were compared between groups differences. In ALL, the only increased FA in the body of corpus callosum (PFWE-corrected = 0.023) and left superior corona radiata (PFWE-corrected = 0.045) were presented. Relative to TDs, pediatric ALL presented a significant decrease in cortical surface area (CSA), thickness (CT), and volume in orbital gyri, supramarginal gyrus, middle temporal gyrus, and superior temporal gyrus (all CWP = 0.01). Additionally, increased CT and CSA were found in lingual gyrus and left sulcus intermedius primus, respectively (all CWP = 0.01). Smaller volumes in pediatric ALL were observed in bilateral thalamus, caudate, hippocampus, and right putamen (PFDR-corrected < 0.05). Widespread brain structural abnormalities were found in new-onset pediatric ALL, which suggest disease itself can cause brain structural injury. This study revealed the altered white matter integrity and gray matter morphology characteristics in childhood acute lymphoblastic leukemia on new-onset stage. It is suggested that there may be structural impairment before chemotherapy. MRI is a sensitive way for early detection on brain structural damage in childhood acute lymphoblastic leukemia.

Pro-atherogenic medical conditions are associated with widespread regional brain metabolite abnormalities in those with alcohol use disorder.

Widespread brain metabolite abnormalities in those with alcohol use disorder (AUD) were reported in numerous studies, but the effects of the pro-atherogenic conditions of hypertension, type 2 diabetes mellitus, hepatitis C seropositivity, and hyperlipidemia on metabolite levels were not considered. These conditions were associated with brain metabolite abnormalities in those without AUD. We predicted treatment-seeking individuals with AUD and pro-atherogenic conditions (Atherogenic+) demonstrate lower regional metabolite markers of neuronal viability [N-acetylaspartate (NAA)] and cell membrane turnover/synthesis [choline-containing compounds (Cho)], compared with those with AUD without pro-atherogenic conditions (Atherogenic-) and healthy controls (CON). Atherogenic+ (n = 59) and Atherogenic- (n = 51) and CON (n = 49) completed a 1.5T proton magnetic resonance spectroscopic imaging study. Groups were compared on NAA, Cho, total creatine, and myoinositol in cortical gray matter (GM), white matter (WM), and select subcortical regions. Atherogenic+ had lower frontal GM and temporal WM NAA than CON. Atherogenic+ showed lower parietal GM, frontal, parietal and occipital WM and lenticular nuclei NAA level than Atherogenic- and CON. Atherogenic- showed lower frontal GM and WM NAA than CON. Atherogenic+ had lower Cho level than CON in the frontal GM, parietal WM, and thalamus. Atherogenic+ showed lower frontal WM and cerebellar vermis Cho than Atherogenic- and CON. Findings suggest proatherogenic conditions in those with AUD were associated with increased compromise of neuronal integrity and cell membrane turnover/synthesis. The greater metabolite abnormalities observed in Atherogenic+ may relate to increased oxidative stress-related compromise of neuronal and glial cell structure and/or impaired arterial vasoreactivity/lumen viability.

Anterior–temporal hippocampal network mechanisms of left angular gyrus-navigated rTMS for memory improvement in aMCI: A sham-controlled study

IntroductionNeuro-navigated repetitive transcranial magnetic stimulation (rTMS) of the left angular gyrus has been broadly investigated for the treatment of amnestic mild cognitive impairment (aMCI). Although abnormalities in two hippocampal networks, the anterior–temporal (AT) and posterior–medial (PM) networks, are consistent with aMCI and are potential therapeutic targets for rTMS, the underlying mechanisms of the therapeutic effects of rTMS on hippocampal network connections remain unknown. Here, we assessed the impact of left angular gyrus rTMS on activity in these networks and explored whether the treatment response was due to the distance between the clinically applied target (the group average optimal site) and the personalized target in patients with aMCI. MethodsSixty subjects clinically diagnosed with aMCI participated in this study after 20 sessions of sham-controlled rTMS targeting the left angular gyrus. Resting-state functional magnetic resonance imaging and neuropsychological assessments were performed before and after rTMS. Functional connectivity alterations in the PM and AT networks were assessed using seed-based functional connectivity analysis and two-factor repeated measures analysis of variance (ANOVA). We then computed the correlations between the functional connectivity changes and clinical rating scales. Finally, we examined whether the Euclidean distance between the clinically applied and personalized targets predicted the subsequent treatment response. ResultsCompared with the sham group, the active rTMS group showed rTMS-induced deactivation of functional connectivity within the medial temporal lobe-AT network, with a negative correlation with episodic memory score changes. Moreover, the active rTMS lowers the interdependency of changes in the PM and AT networks. Finally, the Euclidean distance between the clinically applied and personalized target distances could predict subsequent network lever responses in the active rTMS group. ConclusionsNeuro-navigated rTMS selectively modulates widespread functional connectivity abnormalities in the PM and AT hippocampal networks in aMCI patients, and the modulation of hippocampal-AT network connectivity can efficiently reverse memory deficits. The results also highlight the necessity of personalized targets for fMRI.

Brain network functional connectivity changes in long illness duration chronic schizophrenia.

Chronic schizophrenia has a course of 5 years or more and has a widespread abnormalities in brain functional connectivity. This study aimed to find characteristic functional and structural changes in a long illness duration chronic schizophrenia (10 years or more). Thirty-six patients with a long illness duration chronic schizophrenia and 38 healthy controls were analyzed by independent component analysis of brain network functional connectivity. Correlation analysis with clinical duration was performed on six resting state networks: auditory network, default mode network, dorsal attention network, fronto-parietal network, somatomotor network, and visual network. The differences in the resting state network between the two groups revealed that patients exhibited enhanced inter-network connections between default mode network and multiple brain networks, while the inter-network connections between somatomotor network, default mode network and visual network were reduced. In patients, functional connectivity of Cuneus_L was negatively correlated with illness duration. Furthermore, receiver operating characteristic curve of functional connectivity showed that changes in Thalamus_L, Rectus_L, Frontal_Mid_R, and Cerebelum_9_L may indicate a longer illness duration chronic schizophrenia. In our study, we also confirmed that the course of disease is significantly associated with specific brain regions, and the changes in specific brain regions may indicate that chronic schizophrenia has a course of 10 years or more.

Mapping the interplay of atrial fibrillation, brain structure, and cognitive dysfunction.

Atrial fibrillation (AF) is associated with an elevated risk of cognitive impairment and dementia. Understanding the cognitive sequelae and brain structural changes associated with AF is vital for addressing ensuing health care needs. We examined 1335 stroke-free individuals with AF and 2683 matched controls using neuropsychological assessments and multimodal neuroimaging. The analysis revealed that individuals with AF exhibited deficits in executive function, processing speed, and reasoning, accompanied by reduced cortical thickness, elevated extracellular free-water content, and widespread white matter abnormalities, indicative of small vessel pathology. Notably, brain structural differences statistically mediated the relationship between AF and cognitive performance. Integrating a comprehensive analysis approach with extensive clinical and magnetic resonance imaging data, our study highlights small vessel pathology as a possible unifying link among AF, cognitive decline, and abnormal brain structure. These insights can inform diagnostic approaches and motivate the ongoing implementation of effective therapeutic strategies. Highlights We investigated neuropsychological and multimodal neuroimaging data of 1335 individuals with atrial fibrillation (AF) and 2683 matched controls. Our analysis revealed AF-associated deficits in cognitive domains of attention, executive function, processing speed, and reasoning. Cognitive deficits in the AF group were accompanied by structural brain alterations including reduced cortical thickness and gray matter volume, alongside increased extracellular free-water content as well as widespread differences of white matter integrity. Structural brain changes statistically mediated the link between AF and cognitive performance, emphasizing the potential of structural imaging markers as a diagnostic tool in AF-related cognitive decline.

Quantitative Imaging Reveals Steatosis and Fibroinflammation in Multiple Organs in People With Type 2 Diabetes: A Real-World Study.

We aimed to determine the extent of multi-organ fat accumulation and fibro-inflammation in individuals living with type 2 diabetes. We deeply phenotyped individuals with type 2 diabetes (134 from secondary care, 69 from primary care) with multi-organ, quantitative multi-parametric MRI and compared with 134 matched controls and 92 normal weight controls. We examined the impact of diabetes duration, obesity status and glycemic control. Ninety-three of the individuals with type 2 diabetes were re-evaluated at 7 months (median). Multi-organ abnormalities were more common in individuals with type 2 diabetes (94%) than in age, BMI-matched healthy or healthy normal weight people. We demonstrated a high burden of combined steatosis and fibro-inflammation, within the liver, pancreas and kidneys (41, 17 and 10%), associated with visceral adiposity (73%) and poor vascular health (82%). Obesity was most closely associated with advanced liver disease, renal and visceral steatosis, and multi-organ abnormalities whilst poor glycaemic control was associated with pancreatic fibro-inflammation. Pharmacological therapies with proven cardiorenal protection improved liver and vascular health unlike conventional glucose-lowering treatments, whilst weight loss or improved glycaemic control reduced multi-organ adiposity (p≤0.01). Quantitative imaging in people with type 2 diabetes highlights widespread organ abnormalities and may provide useful risk and treatment stratification.

Widespread White Matter Abnormalities in Concussed Athletes Detected by 7T Diffusion Magnetic Resonance Imaging.

Sports-related concussions may cause white matter injuries and persistent post-concussive symptoms (PPCS). We hypothesized that athletes with PPCS would have neurocognitive impairments and white matter abnormalities that could be revealed by advanced neuroimaging using ultra-high field strength diffusion tensor (DTI) and diffusion kurtosis (DKI) imaging metrics and cerebrospinal fluid (CSF) biomarkers. A cohort of athletes with PPCS severity limiting the ability to work/study and participate in sport school and/or social activities for ≥6 months completed 7T magnetic resonance imaging (MRI) (morphological T1-weighed volumetry, DTI and DKI), extensive neuropsychological testing, symptom rating, and CSF biomarker sampling. Twenty-two athletes with PPCS and 22 controls were included. Concussed athletes performed below norms and significantly lower than controls on all but one of the psychometric neuropsychology tests. Supratentorial white and gray matter, as well as hippocampal volumes did not differ between concussed athletes and controls. However, of the 72 examined white matter tracts, 16% of DTI and 35% of DKI metrics (in total 28%) were significantly different between concussed athletes and controls. DKI fractional anisotropy and axial kurtosis were increased, and DKI radial diffusivity and radial kurtosis decreased in concussed athletes when compared with controls. CSF neurofilament light (NfL; an axonal injury marker), although not glial fibrillary acidic protein, correlated with several diffusion metrics. In this first 7T DTI and DKI study investigating PPCS, widespread microstructural alterations were observed in the white matter, correlating with CSF markers of axonal injury. More white matter changes were observed using DKI than using DTI. These white matter alterations may indicate persistent pathophysiological processes following concussion in sport.

Influences of amyloid-β and tau on white matter neurite alterations in dementia with Lewy bodies

Dementia with Lewy bodies (DLB) is a neurodegenerative condition often co-occurring with Alzheimer’s disease (AD) pathology. Characterizing white matter tissue microstructure using Neurite Orientation Dispersion and Density Imaging (NODDI) may help elucidate the biological underpinnings of white matter injury in individuals with DLB. In this study, diffusion tensor imaging (DTI) and NODDI metrics were compared in 45 patients within the dementia with Lewy bodies spectrum (mild cognitive impairment with Lewy bodies (n = 13) and probable dementia with Lewy bodies (n = 32)) against 45 matched controls using conditional logistic models. We evaluated the associations of tau and amyloid-β with DTI and NODDI parameters and examined the correlations of AD-related white matter injury with Clinical Dementia Rating (CDR). Structural equation models (SEM) explored relationships among age, APOE ε4, amyloid-β, tau, and white matter injury. The DLB spectrum group exhibited widespread white matter abnormalities, including reduced fractional anisotropy, increased mean diffusivity, and decreased neurite density index. Tau was significantly associated with limbic and temporal white matter injury, which was, in turn, associated with worse CDR. SEM revealed that amyloid-β exerted indirect effects on white matter injury through tau. We observed widespread disruptions in white matter tracts in DLB that were not attributed to AD pathologies, likely due to α-synuclein-related injury. However, a fraction of the white matter injury could be attributed to AD pathology. Our findings underscore the impact of AD pathology on white matter integrity in DLB and highlight the utility of NODDI in elucidating the biological basis of white matter injury in DLB.

Abstract 4293: Chromosomal instability causes epigenetic aberrations in cancer

Abstract Chromosomal instability and changes in the epigenome are defining features in most metastatic cancers. Our research links chromosomal missegregation, their containment in micronuclei, and subsequent rupture of the micronuclear envelope to histone post-translational modification aberrations. This relationship was across all tested human and murine cancer cell lines, as well as non-transformed cells. Furthermore, we discovered that the observed changes in histone PTMs were caused by either micronuclear rupture or the persistence of histone PTM status during cell division. Moreover, we revealed substantial chromatin accessibility differences in micronuclei. Notably, there is a distinct bias in chromatin accessibility between promoter regions compared to distal and intergenic regions of the genome, which aligned well with observed changes in histone modifications. The induction of chromosomal instability leads to widespread, heterogeneous, and heritable abnormalities in the epigenetic landscape of cancer cells. Therefore, on top of genomic copy number changes, chromosomal instability causes epigenetic reprogramming, which adds another layer to cancer heterogeneity. Citation Format: Albert S. Agustinus, Duaa Al-Rawi, Bhargavi Dameracharla, Ramya Raviram, Bailey S. Jones, Stephanie Stransky, Lorenzo Scipioni, Jens Luebeck, Melody Di Bona, Danguole Norkunaite, Robert M. Myers, Mercedes Duran, Seongmin Choi, Britta Weigelt, Shira Yomtoubian, Andrew McPherson, Eleonore Toufektchan, Kristina Keuper, Paul S. Mischel, Vivek Mittal, Sohrab P. Shah, John Maciejowski, Zuzana Storchova, Enrico Gratton, Peter Ly, Dan Landau, Mathieu F. Bakhoum, Richard P. Koche, Simone Sidoli, Vineet Bafna, Yael David, Samuel F. Bakhoum. Chromosomal instability causes epigenetic aberrations in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4293.

A latent clinical-anatomical dimension relating metabolic syndrome to brain structure and cognition.

The link between metabolic syndrome (MetS) and neurodegenerative as well as cerebrovascular conditions holds substantial implications for brain health in at-risk populations. This study elucidates the complex relationship between MetS and brain health by conducting a comprehensive examination of cardiometabolic risk factors, brain morphology, and cognitive function in 40,087 individuals. Multivariate, data-driven statistics identified a latent dimension linking more severe MetS to widespread brain morphological abnormalities, accounting for up to 71% of shared variance in the data. This dimension was replicable across sub-samples. In a mediation analysis, we could demonstrate that MetS-related brain morphological abnormalities mediated the link between MetS severity and cognitive performance in multiple domains. Employing imaging transcriptomics and connectomics, our results also suggest that MetS-related morphological abnormalities are linked to the regional cellular composition and macroscopic brain network organization. By leveraging extensive, multi-domain data combined with a dimensional stratification approach, our analysis provides profound insights into the association of MetS and brain health. These findings can inform effective therapeutic and risk mitigation strategies aimed at maintaining brain integrity.

A latent clinical-anatomical dimension relating metabolic syndrome to brain structure and cognition

The link between metabolic syndrome (MetS) and neurodegenerative as well as cerebrovascular conditions holds substantial implications for brain health in at-risk populations. This study elucidates the complex relationship between MetS and brain health by conducting a comprehensive examination of cardiometabolic risk factors, brain morphology, and cognitive function in 40,087 individuals. Multivariate, data-driven statistics identified a latent dimension linking more severe MetS to widespread brain morphological abnormalities, accounting for up to 71% of shared variance in the data. This dimension was replicable across sub-samples. In a mediation analysis, we could demonstrate that MetS-related brain morphological abnormalities mediated the link between MetS severity and cognitive performance in multiple domains. Employing imaging transcriptomics and connectomics, our results also suggest that MetS-related morphological abnormalities are linked to the regional cellular composition and macroscopic brain network organization. By leveraging extensive, multi-domain data combined with a dimensional stratification approach, our analysis provides profound insights into the association of MetS and brain health. These findings can inform effective therapeutic and risk mitigation strategies aimed at maintaining brain integrity.

Functional correlates of cognitive performance and working memory in temporal lobe epilepsy: Insights from task-based and resting-state fMRI.

Temporal lobe epilepsy (TLE) is a common form of medically intractable epilepsy. Although seizures originate in mesial temporal structures, there are widespread abnormalities of gray and white matter beyond the temporal lobes that negatively impact functional networks and cognition. Previous studies have focused either on the global impact on functional networks, or on the functional correlates of specific cognitive abilities. Here, we use a two-pronged approach to evaluate the link between whole-brain functional connectivity (FC) anomalies to overall cognitive performance, and how such abnormal connectivity alters the fronto-parietal brain regions involved in working memory (WMem), a cognitive disability often reported by TLE patients. We evaluated 31 TLE patients and 35 healthy subjects through extensive cognitive testing, resting-state functional magnetic resonance imaging (RS-fMRI), and task-based fMRI using Sternberg's task to evaluate WMem. As a group, TLE patients displayed cognitive abnormalities across different domains, although considerable within-group variability was identified. TLE patients showed disruptions of functional networks between and within the default mode network (DMN) and task-positive networks (TPN) resulting in associations with cognitive performance. Furthermore, during the WMem task, TLE patients showed abnormal activity of fronto-parietal regions that were associated with other forms of memory, and alterations of seed-based connectivity analyses. Our results show that different degrees of abnormal functional brain activity and connectivity are related to the severity of disabilities across cognitive spheres. Differential co-activation patterns between patients and healthy subjects suggest potential compensatory mechanisms to preserve adequate cognitive performance.

Alterations of Functional Connectivity Dynamics in Affective and Psychotic Disorders

BackgroundPatients with psychosis and patients with depression exhibit widespread neurobiological abnormalities. The analysis of dynamic functional connectivity (dFC) allows for the detection of changes in complex brain activity patterns, providing insights into common and unique processes underlying these disorders. MethodsWe report the analysis of dFC in a large sample including 127 patients at clinical high risk for psychosis, 142 patients with recent-onset psychosis, 134 patients with recent-onset depression, and 256 healthy control participants. A sliding window–based technique was used to calculate the time-dependent FC in resting-state magnetic resonance imaging data, followed by clustering to reveal recurrent FC states in each diagnostic group. ResultsWe identified 5 unique FC states, which could be identified in all groups with high consistency (mean r = 0.889 [SD = 0.116]). Analysis of dynamic parameters of these states showed a characteristic increase in the lifetime and frequency of a weakly connected FC state in patients with recent-onset depression (p < .0005) compared with the other groups and a common increase in the lifetime of an FC state characterized by high sensorimotor and cingulo-opercular connectivities in all patient groups compared with the healthy control group (p < .0002). Canonical correlation analysis revealed a mode that exhibited significant correlations between dFC parameters and clinical variables (r = 0.617, p < .0029), which was associated with positive psychosis symptom severity and several dFC parameters. ConclusionsOur findings indicate diagnosis-specific alterations of dFC and underline the potential of dynamic analysis to characterize disorders such as depression and psychosis and clinical risk states.

Ventricular tachycardia ablation after myocardial infarction guided by cardiac magnetic resonance/multidetector computed tomography image integration

Abstract INTRODUCTION The persistent challenge of ventricular tachycardia (VT) ablation lies in the elevated morbidity and mortality due to the underlying disease progression and the complexity of the arrhythmogenic substrate. As imaging methods are evolving, substrate-based VT ablation is moving closer to the realm of precision medicine. CASE PRESENTATION A 52-year-old patient with a history of hypertension, type II diabetes mellitus, hyperlipidemia, and stage IIIB chronic kidney disease was referred to our hospital for sustained monomorphic VT. Upon admission, the patient was hemodynamically stable. Laboratory results indicated mild anemia, moderate renal dysfunction, and normal myocardial enzymes. ECG during sinus rhythm showed widespread repolarization abnormalities in the apical and postero-lateral leads. Echocardiography revealed mild left ventricular dysfunction and coronary angiography confirmed significant lesions in multiple coronary arteries that were treated with drug-eluting stents (DES). Cardiac MRI showed relatively limited areas of old myocardial infarctions in the left circumflex artery and left anterior descending artery territories, therefore we decided to perform VT ablation. We used a Carto 3 Biosense Webster electro-anatomical mapping system (EAM) guided by fusion imaging (cardiac MRI and multidetector computed tomography - MDCT) with the aid of ADAS 3D software. The voltage map created during sinus rhythm, was concordant with the lesions identified on LGE-CMR. Radiofrequency (RF) catheter ablation targeted abnormal signals from the EAM, which were identified based on conduction channels (CCs) from the fusion imaging. There was complete VT non-inducibility at programmed ventricular stimulation (PVS). At the 3-month follow-up, echocardiography showed a slight improvement in LVEF and repeated PVS proved persistent ventricular arrhythmia non-inducibility. CONCLUSION Substrate-based VT ablation in structural heart disease has greatly improved by high-resolution substrate imaging with detailed anatomy, allowing successful personalized treatment. There is room for further improvement in the near future with the contribution of artificial intelligence, possibly with a more targeted and automated VT ablation.

Variational mode decomposition-based EEG analysis for the classification of disorders of consciousness.

Aberrant alterations in any of the two dimensions of consciousness, namely awareness and arousal, can lead to the emergence of disorders of consciousness (DOC). The development of DOC may arise from more severe or targeted lesions in the brain, resulting in widespread functional abnormalities. However, when it comes to classifying patients with disorders of consciousness, particularly utilizing resting-state electroencephalogram (EEG) signals through machine learning methods, several challenges surface. The non-stationarity and intricacy of EEG data present obstacles in understanding neuronal activities and achieving precise classification. To address these challenges, this study proposes variational mode decomposition (VMD) of EEG before feature extraction along with machine learning models. By decomposing preprocessed EEG signals into specified modes using VMD, features such as sample entropy, spectral entropy, kurtosis, and skewness are extracted across these modes. The study compares the performance of the features extracted from VMD-based approach with the frequency band-based approach and also the approach with features extracted from raw-EEG. The classification process involves binary classification between unresponsive wakefulness syndrome (UWS) and the minimally conscious state (MCS), as well as multi-class classification (coma vs. UWS vs. MCS). Kruskal-Wallis test was applied to determine the statistical significance of the features and features with a significance of p < 0.05 were chosen for a second round of classification experiments. Results indicate that the VMD-based features outperform the features of other two approaches, with the ensemble bagged tree (EBT) achieving the highest accuracy of 80.5% for multi-class classification (the best in the literature) and 86.7% for binary classification. This approach underscores the potential of integrating advanced signal processing techniques and machine learning in improving the classification of patients with disorders of consciousness, thereby enhancing patient care and facilitating informed treatment decision-making.

Multi-level profiling unravels mitochondrial dysfunction in myotonic dystrophy type 2

Myotonic dystrophy type 2 (DM2) is an autosomal-dominant multisystemic disease with a core manifestation of proximal muscle weakness, muscle atrophy, myotonia, and myalgia. The disease-causing CCTG tetranucleotide expansion within the CNBP gene on chromosome 3 leads to an RNA-dominated spliceopathy, which is currently untreatable. Research exploring the pathophysiological mechanisms in myotonic dystrophy type 1 has resulted in new insights into disease mechanisms and identified mitochondrial dysfunction as a promising therapeutic target. It remains unclear whether similar mechanisms underlie DM2 and, if so, whether these might also serve as potential therapeutic targets. In this cross-sectional study, we studied DM2 skeletal muscle biopsy specimens on proteomic, molecular, and morphological, including ultrastructural levels in two separate patient cohorts consisting of 8 (explorative cohort) and 40 (confirmatory cohort) patients. Seven muscle biopsy specimens from four female and three male DM2 patients underwent proteomic analysis and respiratory chain enzymology. We performed bulk RNA sequencing, immunoblotting of respiratory chain complexes, mitochondrial DNA copy number determination, and long-range PCR (LR-PCR) to study mitochondrial DNA deletions on six biopsies. Proteomic and transcriptomic analyses revealed a downregulation of essential mitochondrial proteins and their respective RNA transcripts, namely of subunits of respiratory chain complexes I, III, and IV (e.g., mt-CO1, mt-ND1, mt-CYB, NDUFB6) and associated translation factors (TACO1). Light microscopy showed mitochondrial abnormalities (e.g., an age-inappropriate amount of COX-deficient fibers, subsarcolemmal accumulation) in most biopsy specimens. Electron microscopy revealed widespread ultrastructural mitochondrial abnormalities, including dysmorphic mitochondria with paracrystalline inclusions. Immunofluorescence studies with co-localization of autophagy (p62, LC-3) and mitochondrial marker proteins (TOM20, COX-IV), as well as immunohistochemistry for mitophagy marker BNIP3 indicated impaired mitophagic flux. Immunoblotting and LR-PCR did not reveal significant differences between patients and controls. In contrast, mtDNA copy number measurement showed a reduction of mtDNA copy numbers in the patient group compared to controls. This first multi-level study of DM2 unravels thus far undescribed functional and structural mitochondrial abnormalities. However, the molecular link between the tetranucleotide expansion and mitochondrial dysfunction needs to be further elucidated.

Alteration of white matter microstructure in patients with sleep disorders after COVID-19 infection

BackgroundThe pathophysiology of coronasomnia remains unclear. This study aimed to investigate changes in white matter (WM) microstructure and inflammatory factors in patients with sleep disorders (SD) characterized by poor sleep quantity, quality, or timing following coronavirus disease 2019 (COVID-19) infection in the acute phase (within one month) and whether these changes could be recovered at 3-month follow-up. Methods29 acute COVID-19 patients with SD (COVID_SD) and 27 acute COVID-19 patients without SD (COVID_NonSD) underwent diffusion tensor imaging (DTI), tested peripheral blood inflammatory cytokines level, and measured Pittsburgh Sleep Quality Index (PSQI), and matched 30 uninfected healthy controls. Analyzed WM abnormalities between groups in acute phase and explored its changes in COVID_SD at 3-month follow-up by using tract-based spatial statistics (TBSS). Correlations between DTI and clinical data were examined using Spearman partial correlation analysis. ResultsBoth COVID_SD and COVID_NonSD exhibited widespread WM microstructure abnormalities. The COVID_SD group showed specific WM microstructure changes in right inferior fronto-occipital fasciculus (IFOF) (lower fractional anisotropy [FA]/axial diffusivity [AD] and higher radial diffusivity [RD]) and left corticospinal tract (CST) (higher FA and lower RD) and higher interleukin-1β (IL-1β) compared with COVID_NonSD group. These WM abnormalities and IL-1β levels were correlated PSQI score. After 3 months, the IFOF integrity and IL-1β levels tended to return to normal accompanied by symptom improvement in the COVID_SD relative to baseline. ConclusionAbnormalities in right IFOF and left CST and elevated IL-1β levels were important neurophenotypes correlated with COVID_SD, which might provide new insights into the pathogenesis of neuroinflammation in SD patients induced by COVID-19.

Gastro-Esophageal Junction Precancerosis: Histological Diagnostic Approach and Pathogenetic Insights.

Barrett's esophagus (BE) was initially defined in the 1950s as the visualization of gastric-like mucosa in the esophagus. Over time, the definition has evolved to include the identification of goblet cells, which confirm the presence of intestinal metaplasia within the esophagus. Chronic gastro-esophageal reflux disease (GERD) is a significant risk factor for adenocarcinoma of the esophagus, as intestinal metaplasia can develop due to GERD. The development of adenocarcinomas related to BE progresses in sequence from inflammation to metaplasia, dysplasia, and ultimately carcinoma. In the presence of GERD, the squamous epithelium changes to columnar epithelium, which initially lacks goblet cells, but later develops goblet cell metaplasia and eventually dysplasia. The accumulation of multiple genetic and epigenetic alterations leads to the development and progression of dysplasia. The diagnosis of BE requires the identification of intestinal metaplasia on histologic examination, which has thus become an essential tool both in the diagnosis and in the assessment of dysplasia's presence and degree. The histologic diagnosis of BE dysplasia can be challenging due to sampling error, pathologists' experience, interobserver variation, and difficulty in histologic interpretation: all these problems complicate patient management. The development and progression of Barrett's esophagus (BE) depend on various molecular events that involve changes in cell-cycle regulatory genes, apoptosis, cell signaling, and adhesion pathways. In advanced stages, there are widespread genomic abnormalities with losses and gains in chromosome function, and DNA instability. This review aims to provide an updated and comprehensible diagnostic approach to BE based on the most recent guidelines available in the literature, and an overview of the pathogenetic and molecular mechanisms of its development.

Brain Structure and Cognitive Dysfunction in Myotonic Dystrophy Type 2 (BraCE‐DM2)

AbstractBackgroundMyotonic dystrophy type 2 (DM2) is a pleiotropic multisystemic disease. Although progressive muscle weakness is the main symptom in DM2, almost two‐third of the patients report cognitive deficits as one of the most disabling symptoms. Emerging evidence has identified tau mis‐splicing and tangle pathology in DM2, which has prompted interest in elucidating the role of tau in DM2‐related cognitive impairment. Previous studies suggest that cerebral white matter (WM) is primarily affected in DM2. However, quantitative brain imaging studies incorporate with cognitive measures are extremely limited.Method3T brain MRIs were acquired in 10 adults with DM2 and 10 gender and age‐matched controls. Brain morphometry and WM integrity were assessed using T1‐MPRAGE and diffusion tensor imaging (DTI) sequences. DTI scalars, including fractional anisotropy (FA), radial diffusivity (RD), axial diffusivity (AD), and median diffusivity (MD) were compared between groups. A comprehensive battery of cognitive and behavioral measures was performed and correlated with MRI measures (Spearman’s Correlation).ResultOf 20 participants (60% female), mean age (62.2 vs. 62.6 years) and education (16.4 vs. 17.5 years) were similar between the two groups. Compared to controls, the DM2 group showed a significant reduction in global measures of cerebral gray matter (GM) volume in both cortex and deep gray structures (mean difference, ‐0.03; p&lt;0.01), but not the WM volume. Widespread abnormalities in DTI measures (lower FA, higher RD) were among the most robust findings in DM2 (mean differences of FA, 0.04; p&lt;0.01 and RD, 0.00004; p&lt;0.01), indicating that the pathology is within WM microstructures. Overall, the DM2 group scored lower than controls in all cognitive domains, particularly executive function (mean difference, ‐12.5; p = 0.04). We found a strong correlation between cerebral FA and a test of executive function (rho = 0.71, p = 0.02). Cerebral FA also showed a moderate correlation with processing speed (rho = 0.50) and apathy evaluation scale (rho = ‐0.43).ConclusionOur pilot data demonstrate robust differences of brain structure, explicitly measures of WM integrity and cerebral GM volume between the DM2 group vs. controls. The strong correlation between cerebral FA and executive function also supports the notion that WM integrity plays an important role in cognitive dysfunction in DM2.