Cerebral White Matter Research Articles

Paracetamol overdose associated with cortical blindness-complicated acute leukoencephalopathy: a case report

Abstract Background Paracetamol is one of the most used antipyretics and analgesics among pediatrics, and its overdose is highly encountered among pediatrics especially in the pre-school age. While it is well-known that paracetamol overdose may lead to toxicities including severe hepatic toxicity, some recent reports have highlighted its “in situ” toxicity on brain tissue at high doses, even in the absence of hepatotoxicity. This can result in acute leukoencephalopathy (AL), coma, or even death. This report describes a case of a child who developed cortical blindness-complicated AL, following a paracetamol overdose. Case presentation An 18-month-old previously healthy girl accidentally ingested 300 mg/kg of paracetamol suspension. After ingestion, the child was in an initial bad condition that has gradually improved. Several days after ingestion, the patient lost her vision, and she remained blind since then despite a newer appreciation to light. The initial brain magnetic resonance imaging (MRI) suggested AL demonstrated as a faint high T2/fluid-attenuated inversion recovery (FLAIR) signal intensity in the cortical and subcortical regions of both parieto-occipital lobes with sulcal effacement and restricted diffusion. After around 3 months, the subsequent brain MRI showed involutional changes that were manifested as a brain volume loss in the same areas with evidence of gyri-form laminar necrosis in both parieto-occipital regions without restricted diffusion. Other brain MRI findings include right cerebral convexity hyperacute subdural hematoma with prominent subarachnoid spaces. Conclusions The child developed cortical blindness-complicated AL following a paracetamol overdose. It is well- known that AL may result from several toxins by their direct and/or indirect effect on the cerebral white matter. However, there is still no enough data in the literature clearly explaining the relation of paracetamol overdose to AL. The generally proposed effect of paracetamol on the brain is mainly justified by the excessive oxidative stress. Further studies at the cellular and genetic levels are still needed to investigate the exact association between paracetamol overdose and AL, as well as the underlying mechanisms involved.

Cerebral white matter myelination is associated with longitudinal changes in processing speed across the adult lifespan

Abstract Myelin's role in processing speed is pivotal, as it facilitates efficient neural conduction. Its decline could significantly affect cognitive efficiency during aging. In this work, myelin content was quantified using our advanced MRI method of myelin water fraction (MWF) mapping. We examined the relationship between MWF at the time of MRI and retrospective longitudinal change in processing speed among 121 cognitively unimpaired participants, aged 22 to 94 years, from the Baltimore Longitudinal Study of Aging and the Genetic and Epigenetic Signatures of Translational Aging Laboratory Testing (mean follow-up duration of 4.3 ± 6.3 years) using linear mixed-effects models, adjusting for demographics. We found that higher MWF values correlated with longitudinally better-maintained processing speed, with particularly significant associations in several white matter regions. Detailed voxel-wise analysis provided further insight into the specific white matter tracts involved. This research underscores the essential role of myelin in preserving processing speed and highlights its potential as a sensitive biomarker for interventions targeting age-related cognitive decline, thereby offering a foundation for preventative strategies in neurological health.

Interhypothalamic adhesions: prevalence, structure, and location-based classification map in pediatric patients undergoing MRI.

Interhypothalamic adhesions (IHAs) have been reported only in the pediatric population, with unknown prevalence and histological composition. We aim to demonstrate their prevalence, assess their persistence through longitudinal imaging, classify IHAs by anatomical distribution, explore their structure, and report associated pathologies. A retrospective review was conducted on consecutive pediatric brain MRI studies obtained between January 2012, and December 2013. The presence of an IHA was only confirmed when observed on at least two planes. For each IHA, cross-sectional area was calculated, and signal intensities were measured at the center on sagittal T2WIs. Signal intensities were also measured in both cerebral white matter and gray matter for normalization and comparison. Patient demographics and clinical information were collected from electronic charts. Out of 1550 patients (0-17.9 years), 33 (19 males, 14 females) had an IHA, resulting in a 2.13% prevalence. Follow-up images were available for 19 IHA-positive patients, and IHAs were again seen in 92% of the follow-up scans (71/77). Normalized IHA signal highly correlated with normalized gray matter signal (r = 0.83, P < 0.001), but not with normalized white matter signal (r = -0.16, p = 0.494). Common co-occurring pathologies included hydrocephalus (n = 9), prematurity (n = 8), and corpus callosum abnormalities (n = 7). All type 3 IHAs (3/3) were accompanied by pituitary pathologies. IHAs have a prevalence of 2.13% in our cohort, and the majority persist in longitudinal studies. They showed gray matter signal intensity and Type 3 IHAs exclusively accompanied pituitary abnormalities.

Cerebral microbleeds linked to structural network disruption and cognitive impairment in white matter hyperintensities.

This study aims to explore the relationship between the cerebral microbleeds (CMBs) and white matter structural network in patients with white matter hyperintensities (WMHs), and the correlation with the cognitive impairment. One hundred and fifty-eight participants with WMHs underwent 3.0 T magnetic resonance imaging scans and neuropsychological assessment. The grouping method included count grading with categories: non-CMBs (n-CMBs), CMBs < 5, and CMBs ≥ 5. Additionally, the distribution of CMBs was considered, distinguishing between strictly lobar CMBs (SL-CMBs) and deep or infratentorial CMBs (DI-CMBs). Diffusion tensor imaging was employed to construct the white matter structural network for each participant. Subsequently, we analyzed the correlations between the topological parameters of network and cognitive performance in individuals with CMBs. Compared with n-CMBs group, both CMBs ≥ 5 and DI-CMBs participants exhibited a significant decreased in global efficiency and increased in characteristic path length. Moreover, in the nodal network metrics, the CMBs ≥ 5 showed the left middle occipital gyrus (MOG.L) of nodal efficiency and nodal shortest path correlated with SCWT-A and MMSE, while in the DI-CMBs groups, the left cuneus (CUN.L) of nodal shortest path correlated with SCWT-A. However, there were no significant neuropsychological correlations observed in the SL-CMBs and CMBs < 5 groups. In this study, patients with a high count (≥5) of CMBs or DI-CMBs are associated with disruptions in the microstructure of the white matter structural network, partially impacting the visual network of occipital lobe and affecting the cognitive function of information processing speed and attention.

Grade prediction of lesions in cerebral white matter using a convolutional neural network.

We established a diagnostic method for cerebral white matter lesions using MRI images and examined the relationship between the MRI images and the medical checkup data. There were approximately 25 MRI images for each patient's head, from the top of the head to near the eyes. To order these images, we defined the unit of axial for convenience. We varied conditions, such as the location and extent of the images to be loaded, into a convolutional neural network model and verified the changes in discrimination performance on the test data. Co-occurrence network diagrams were also used to determine the relationship between the grade of cerebral white matter lesions and the biochemical test items, which were treated as categorical variables, the progression of cerebral white matter lesions, and patient health status. The convolutional neural network showed the highest discrimination performance when the images were loaded into the model with 80 pixels per side, axial from 9 to 15, along with FLAIR and T1-weighted images. The area under the curve for each grade was 0.9814 for grade 0, 0.9800 for grade 1, 0.9905 for grade 2, 0.9977 for grade 3, and 0.9998 for grade 4. In the co-occurrence network diagram, patients with no or mild cerebral white matter lesions, such as grade 0 and grade 1, had near normal blood pressure, whereas grade 2 patients were closer to (isolated) systolic hypertension. This indicates that patients with higher-grade cerebral white matter lesions tend to experience more severe hypertension.

Exploring subcortical pathology and processing speed in neuromyelitis optica spectrum disorder with myelin water imaging.

Neuromyelitis optica spectrum disorder (NMOSD) affects the optic nerves and spinal cord but can also cause focal brain inflammation. Subcortical pathology may contribute to the etiology of cognitive deficits in NMOSD. Using myelin water imaging, we investigated cerebral normal-appearing white matter (NAWM) and thalamic metrics and their association with cognition in NMOSD participants compared to healthy controls (HC). Seventeen NMOSD participants and 21 HC were scanned on a 3.0-Tesla MRI scanner using a multicomponent driven-equilibrium single-pulse observation of T1 and T2 protocol. Tissue compartment and thalamic volumes (normalized to intracranial volume), T1 relaxation time, and myelin water fraction (MWF) were reported. Eleven NMOSD participants underwent the Symbol Digit Modalities Test (SDMT) for cognitive evaluation. Group comparisons were performed using Student's t-test. The association between thalamic metrics and SDMT score was assessed using multiple regression analysis with age as a covariate. Compared to HC, NMOSD participants had reduced white matter volume (-14.2%, p<.0001), increased T1 relaxation time (+2.29%, p=.022), and lower MWF (-3.64%, p=.024) in NAWM. NMOSD group had a trend for smaller thalamic volumes than HC (-5.52%, p=.082) and no differences in thalamic MWF (p=.258) or T1 (p=.714). Thalamic T1 predicted SDMT score (adjusted R2=.51, p=.04) when controlling for age. NAWM in NMOSD demonstrates diffuse abnormalities with increased water content and demyelination, suggesting a diffuse disease process overlooked by focal inflammation measures. Increased water content, as a biomarker for diffuse thalamic pathology, may partially explain cognitive impairment in NMOSD.

Cerebrospinal fluid neurofilament light chain levels in children with acquired demyelinating syndrome

ObjectiveTo study the cerebrospinal fluid (CSF) neurofilament light chain (NfL) in pediatric acquired demyelinating syndrome (ADS) and its association with factors of laboratory and imaging results.MethodsWe analyzed clinical data from children with ADS collected from May 2020 to January 2021 at the Department of Neurology of Guangzhou Women and Children's Medical Center. Enzyme-linked immunosorbent assays were used to detect the CSF NfL of patients.ResultsThirty pediatric ADS patients (17 male, 13 female) were included in the study. The most frequent diagnosis was uncategorized ADS (36.7%, 11/30), followed by acute disseminating encephalomyelitis (ADEM) (23.3%, 7/30), myelin oligodendrocyte glycoprotein antibody-associated disorder (MOGAD) (20.0%, 6/30), NMO (6.7%, 2/30), multiple sclerosis (MS) (6.7%, 2/30), and neuromyelitis optic spectrum disorders (NMOSD) (6.7%, 2/30). The median CSF NfL for the first time was 7,425.28 pg/ml (interquartile range, 1,273.51, &amp;gt;10,000 pg/ml). CSF NfL increase over normal value (&amp;lt;290.00 pg/ml for people younger than 30 years old) was seen in 98.7% of patients. Patients were divided into uncategorized ADS, ADEM, MOGAD, and MS/NMO/NMOSD groups, with no significant difference in CSF NfL between each group. The CSF NfL positively correlated with the immunoglobulin (Ig) G (ρ = 0.473) and IgE (ρ = 0.366). However, the CSF NfL did not correlate with CSF white blood count and CSF protein. Furthermore, there was no significant difference between patients with oligoclonal bands positive and without. The CSF NfL negatively correlated with interferon γ (ρ = −0.501), CD45 + CD3+ T (ρ = −0.466), CD45 + CD3 + CD4+ T (ρ = −0.466), and CD45 + CD3 + CD8+ T cells (ρ = −0.521). However, it did not correlate with CD45 + CD19+ B cells. CSF NfL in patients with cerebral white matter lesions in MRI was higher than in patients without. Moreover, the CSF NfL positively correlated with the number of brain MRI locations (ρ = 0.362). Nine patients underwent multiple detections of CSF NfL, and their CSF NfL for the last detection was not significantly different from the first.ConclusionsThe CSF NfL increases significantly in pediatric ADS, and it can be a biomarker of neuro-axonal injury and a good indication of the extent of lesions.

Genetic risk factors underlying white matter hyperintensities and cortical atrophy

White matter hyperintensities index structural abnormalities in the cerebral white matter, including axonal damage. The latter may promote atrophy of the cerebral cortex, a key feature of dementia. Here, we report a study of 51,065 individuals from 10 cohorts demonstrating that higher white matter hyperintensity volume associates with lower cortical thickness. The meta-GWAS of white matter hyperintensities-associated cortical ‘atrophy’ identifies 20 genome-wide significant loci, and enrichment in genes specific to vascular cell types, astrocytes, and oligodendrocytes. White matter hyperintensities-associated cortical ‘atrophy’ showed positive genetic correlations with vascular-risk traits and plasma biomarkers of neurodegeneration, and negative genetic correlations with cognitive functioning. 15 of the 20 loci regulated the expression of 54 genes in the cerebral cortex that, together with their co-expressed genes, were enriched in biological processes of axonal cytoskeleton and intracellular transport. The white matter hyperintensities-cortical thickness associations were most pronounced in cortical regions with higher expression of genes specific to excitatory neurons with long-range axons traversing through the white matter. The meta-GWAS-based polygenic risk score predicts vascular and all-cause dementia in an independent sample of 500,348 individuals. Thus, the genetics of white matter hyperintensities-related cortical atrophy involves vascular and neuronal processes and increases dementia risk.

Modifiable dementia risk associated with smaller white matter volume and altered 1/f aperiodic brain activity: cross-sectional insights from the LEISURE study.

The rising prevalence of dementia necessitates identifying early neurobiological markers of dementia risk. Reduced cerebral white matter volume and flattening of the slope of the electrophysiological 1/f spectral power distribution provide neurobiological markers of brain ageing alongside cognitive decline. However, their association with modifiable dementia risk remains to be understood. A cross-sectional sample of 98 healthy older adults (79 females, mean age = 65.44) underwent structural magnetic resonance imaging (sMRI), resting-state electroencephalography (EEG), cognitive assessments and dementia risk scoring using the CogDrisk framework. Univariate and multivariate linear regression models were conducted to investigate the relationships between modifiable dementia risk and sMRI brain volumes, the exponent of EEG 1/f spectral power, and cognition, whilst controlling for non-modifiable factors. Smaller global white matter volume (F(1,87) = 6.884, R2 = 0.073, P = .010), and not grey (F(1,87) = 0.540, R2 = 0.006, P = .468) or ventricle volume (F(1,87) = 0.087, R2 = 0.001, P = .769), was associated with higher modifiable dementia risk. A lower exponent, reflecting a flatter 1/f spectral power distribution, was associated with higher dementia risk at frontal (F(1,92) = 4.096, R2 = 0.043, P = .046) but not temporal regions. No significant associations were found between cognitive performance and dementia risk. In multivariate analyses, both white matter volume and the exponent of the 1/f spectral power distribution independently associated with dementia risk. Structural and functional neurobiological markers of early brain ageing, but not cognitive function, are independently associated with modifiable dementia risk in healthy older adults.

A Site-Wise Reliability Analysis of the ABCD Diffusion Fractional Anisotropy and Cortical Thickness: Impact of Scanner Platforms.

The Adolescent Brain and Cognitive Development (ABCD) project is the largest study of adolescent brain development. ABCD longitudinally tracks 11,868 participants aged 9-10 years from 21 sites using standardized protocols for multi-site MRI data collection and analysis. While the multi-site and multi-scanner study design enhances the robustness and generalizability of analysis results, it may also introduce nonbiological variances including scanner-related variations, subject motion, and deviations from protocols. ABCD imaging data were collected biennially within a period of ongoing maturation in cortical thickness and integrity of cerebral white matter. These changes can bias the classical test-retest methodologies, such as intraclass correlation coefficients (ICC). We developed a site-wise adaptive ICC (AICC) to evaluate the reliability of imaging-derived phenotypes while accounting for ongoing brain development. AICC iteratively estimates the population-level age-related brain development trajectory using a weighted mixed model and updates age-corrected site-wise reliability until convergence. We evaluated the test-retest reliability of regional fractional anisotropy (FA) measures from diffusion tensor imaging and cortical thickness (CT) from structural MRI data for each site. The mean AICC for 20 FA tracts across sites was 0.61 ± 0.19, lower than the mean AICC for CT in 34 regions across sites, 0.76 ± 0.12. Remarkably, sites using Siemens scanners consistently showed significantly higher AICC values compared with those using GE/Philips scanners for both FA (AICC = 0.71 ± 0.12 vs. 0.46 ± 0.17, p < 0.001) and CT (AICC = 0.80 ± 0.10 vs. 0.69 ± 0.11, p < 0.001). These findings demonstrate site-and-scanner related variations in data quality and underscore the necessity for meticulous data curation in subsequent association analyses.

Novel Gene Mutation Variant in Hypomyelinating Leukodystrophy-8: A Case Report

The incidence of hypomyelinating leukodystrophies is approximately 1 in every 250,000–500,000 individuals in the population. Hypomyelinating leukodystrophy-8 (HLD-8) is characterized by classical clinical features, including modest intellectual deficits and early-onset progressive cerebellar ataxia, with or without oligodontia and/or hypogonadotropic hypogonadism. In this case report, we present a 34-year-old male who experienced gradually progressive behavioral and memory disturbances over the past 10 years, accompanied by imbalance while walking and complex partial seizures. The patient also exhibited oligodontia and moderate intellectual disability (IQ score: 45). Spasticity was observed in the lower limbs, with exaggerated deep tendon reflexes in all four limbs, and bilaterally extensor plantar responses were noted. Sensory examination results were within normal limits. Bilateral cerebellar signs were present, including gaze-evoked nystagmus in all directions, which was non-fatigable. MRI brain revealed generalized cerebral and cerebellar atrophy, as well as diffuse hyperintensities in T2-weighted images (T2W) and fluid-attenuated inversion recovery (FLAIR) in the bilateral cerebral white matter, with no basal ganglia involvement. The sagittal T1-weighted image (T1W) showed diffuse thinning of the corpus callosum. Whole-exome sequencing revealed a novel variant mutation of the POLR3B gene in HLD-8, specifically in Exon 20 [c.2125A&gt;G (p.Met709Val)] and Exon 23 [c.2699G&gt;A (p.Arg900His)]. Very few case reports and variant mutations on the POLR3B gene on chromosome 12q23.3 have been reported thus far.

Peripapillary vessels density is closely related to cerebral white matter hyperintensities: An OCTA study.

Chronic cerebral hypoperfusion triggers the development of white matter hyperintensities (WMHs), common in cerebral small vessel disease (CSVD). However, conventional imaging techniques cannot visualize cerebral small vessels. The retina, a direct extension of the central nervous system, has an unclear correlation with WMHs. This study employs Optical coherence tomographic angiography (OCTA) to investigate vascular changes in the retina and explore its correlation with WMHs, aiming to provide a new method for assessing perfusion in early ischemic brain WMHs. Forty-nine patients with WMHs were stratified into mild and moderate/severe WMHs groups based on MRI findings, utilizing the Fazekas and Scheltens scales. OCTA assessed fundus vessel microcirculation. Logistic regression analyzed the correlation between ocular fundus microcirculation and WMH severity and location. Additionally, ROC curves evaluated the diagnostic efficacy of each fundus vascular microcirculation index in determining WMH severity. After adjusting for multiple confounders, finding consistently indicated that the moderate/ severe WMHs group exhibited lower vessel density (VD) in the superior quadrant of the inner peripapillary region compared to the mild group [OR = 0.487, CI (0.255,0.929), p < 0.05]. ROC curves revealed that when combined with age, diabetes, and superior quadrant VD of the inner peripapillary region, specificity could be increased to 94.1%. Peripapillary vessel density correlates closely with the severity of cerebral WMHs. Early morphological changes due to chronic hypoperfusion may initiate from the inner layer of the optic disc, and OCTA could offer a novel method for evaluating blood perfusion in ischemic WMHs.

Effect of nelonemdaz for patients with out-of-hospital cardiac arrest: the AWAKE phase II randomised clinical trial

Abstract Background Hypoxic brain injury is a major hurdle that limits the survival of out-of-hospital cardiac arrest (OHCA). Nelonemdaz is a dual-target neuroprotectant, serving as a moderate NR2B-selective N-methyl-D-aspartate (NMDA) receptor antagonist while also exhibiting potent free radical scavenger properties. This dual neuroprotective action of nelonemdaz has the potential to reduce hypoxic brain injury in OHCA. We investigated the efficacy and safety of nelonemdaz for patients with OHCA. Methods AWAKE trial was a double-blind, placebo-controlled, randomised, multicentre phase II trial at 5 sites in South Korea. OHCA patients undergoing targeted temperature management were randomly assigned to high-dose (5250 mg), low-dose (3250 mg), and placebo groups at a 1:1:1 ratio. The primary outcome was the blood level of neuron-specific enolase (NSE) after 4th administration of drug. Secondary outcomes comprised blood biomarkers including neuron specific enolase (NSE) and S100beta, brain magnetic resonance imaging (MRI), and Cerebral Performance Category (CPC) and Modified Rankin Scale (mRS) up to day 90. Safety is assessed by serious adverse event. Findings: A total of 105 patients were enrolled between November 18, 2018 to February 23, 2023. Patients with a median age of 61 years and 82% male were assigned to the high-dose (N=37), low-dose (N=35), and placebo (N=33) groups. Primary outcome was evaluated in 93 patients. There was no difference of neuron specific enolase (NSE, ng/mL), which served as the primary endpoint, between high-dose (median and interquartile range; 23·7, 15·0–69·9) and placebo (17·5, 13·6–113·0) groups and also between low-dose (26·6, 16·2–83·4) versus placebo groups (all p&amp;gt;0·05). Among secondary outcomes, fractional anisotropy of brain MRI was significantly higher in high-dose group compared to placebo group (0·465, 0·449–0·485 versus 0·441, 0·431–0·464; p=0·028), and was not different between low-dose (0·462, 0·439–0·480) and placebo groups (p&amp;gt;0·05). At day 90, the common odds ratio (95% confidence interval) indicating a favourable shift in the modified Rankin Scale was 1·25 (0·48–3·24) and 1·22 (0·47–3·20) in the high-dose and low-dose groups respectively, compared to placebo group (all p&amp;gt;0·05). No serious adverse events were reported. Interpretation: Nelonemdaz did not reduced blood NSE level of OHCA patients. However, patients treated with high-dose nelonemdaz showed better fractional anisotropy that suggests reduced cerebral white matter damage. Patients treated with nelonemdaz also showed a favourable tendency of neurological recovery at day 90 without significant adverse effects. These results justify the initiation of a large-scale phase III trial.Neurological function up to day 90

Pediatric CNS-isolated hemophagocytic lymphohistiocytosis with brain hemorrhages: a case report

BackgroundHemophagocytic lymphohistiocytosis (HLH) is an inherited syndrome characterized by immune dysregulation. Central nervous system (CNS)-isolated disease is a rare presentation of familial HLH. We present a case of pediatric CNS-isolated HLH with a presentation complicated by unusual hemorrhagic intraparenchymal lesions.Case PresentationA 15-year-old male presented with ataxia and MRI findings of multiple hemorrhagic lesions in his cerebral white matter, brainstem, and cerebellum, suggestive of vasculitis. After failing to improve with steroids and plasmapheresis, and progression to acute neurologic decompensation, new brainstem hemorrhages were noted. Further workup revealed 2 PRF1 mutations, confirming a diagnosis of familial CNS-HLH. He was later found to have a platelet granule defect, explaining his atypical neuroradiologic findings. The patient received treatment per the HLH-1994 protocol and underwent stem cell transplantation. Two years post-transplant, his perforin expression is nearly normal and his neurologic deficits have significantly improved.ConclusionsThis case illustrates the variability in presentation of isolated CNS-HLH. Although rare, it is important to include this diagnosis on the differential in patients with CNS hemorrhagic lesions. If initial diagnostic studies remain inconclusive or response to early treatments is poor, CNS-HLH should be considered, as delay in diagnosis and treatment significantly affects morbidity and mortality.

Cross-modality image translation of 3 Tesla Magnetic Resonance Imaging to 7 Tesla using Generative Adversarial Networks.

The rapid advancements in magnetic resonance imaging (MRI) technology have precipitated a new paradigm wherein cross-modality data translation across diverse imaging platforms, field strengths, and different sites is increasingly challenging. This issue is particularly accentuated when transitioning from 3 Tesla (3T) to 7 Tesla (7T) MRI systems. This study proposes a novel solution to these challenges using generative adversarial networks (GANs)-specifically, the CycleGAN architecture- to create synthetic 7T images from 3T data. Employing a dataset of 1112 and 490 unpaired 3T and 7T MR images, respectively, we trained a 2-dimensional (2D) CycleGAN model, evaluating its performance on a paired dataset of 22 participants scanned at 3T and 7T. Independent testing on 22 distinct participants affirmed the model's proficiency in accurately predicting various tissue types, encompassing cerebral spinal fluid, gray matter, and white matter. Our approach provides a reliable and efficient methodology for synthesizing 7T images, achieving a median Dice of 6.82%,7,63%, and 4.85% for Cerebral Spinal Fluid (CSF), Gray Matter (GM), and White Matter (WM), respectively, in the testing dataset, thereby significantly aiding in harmonizing heterogeneous datasets. Furthermore, it delineates the potential of GANs in amplifying the contrast-to-noise ratio (CNR) from 3T, potentially enhancing the diagnostic capability of the images. While acknowledging the risk of model overfitting, our research underscores a promising progression towards harnessing the benefits of 7T MR systems in research investigations while preserving compatibility with existent 3T MR data. This work was previously presented at the ISMRM 2021 conference (Diniz, Helmet, Santini, Aizenstein, & Ibrahim, 2021).

Spectrum of delayed post-hypoxic leukoencephalopathy syndrome: A systematic review

BACKGROUND Delayed post hypoxic leukoencephalopathy syndrome (DPHLS), also known as Grinker’s myelinopathy, is a rare but significant neurological condition that manifests days to weeks after a hypoxic event. Characterized by delayed onset of neurological and cognitive deficits, DPHLS presents substantial diagnostic and therapeutic challenges. AIM To consolidate current knowledge on pathophysiology, clinical features, diagnostic approaches, and management strategies for DPHLS, providing a comprehensive overview and highlighting gaps for future research. METHODS Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes guidelines, we systematically searched PubMed, ScienceDirect and Hinari databases using terms related to delayed post-hypoxic leukoencephalopathy. Inclusion criteria were original research articles, case reports, and case series involving human subjects with detailed clinical, neuroimaging, or pathological data on DPHLS. Data were extracted on study characteristics, participant demographics, clinical features, neuroimaging findings, pathological findings, treatment, and outcomes. The quality assessment was performed using the Joanna Briggs Institute critical appraisal checklist. RESULTS A total of 73 cases were reviewed. Common comorbidities included schizoaffective disorder, bipolar disorder, hypertension, and substance use disorder. The primary causes of hypoxia were benzodiazepine overdose, opioid overdose, polysubstance overdose, and carbon monoxide (CO) poisoning. Symptoms frequently include decreased level of consciousness, psychomotor agitation, cognitive decline, parkinsonism, and encephalopathy. Neuroimaging commonly revealed diffuse T2 hyperintensities in cerebral white matter, sometimes involving the basal ganglia and the globus pallidus. Magnetic resonance spectroscopy often showed decreased N-acetylaspartate, elevated choline, choline-to-creatinine ratio, and normal or elevated lactate. Treatment is often supportive, including amantadine, an antioxidant cocktail, and steroids. Hyperbaric oxygen therapy may be beneficial in those with CO poisoning. Parkinsonism was often treated with levodopa. Most of the patients had substantial recovery over the course of months and many cases had some residual neurocognitive deficits. CONCLUSION DPHLS remains a complex and multifaceted condition with various etiologies and clinical manifestations. Early recognition and appropriate management are crucial to improving patient outcomes. Future research should focus on standardizing diagnostic criteria, using advanced imaging techniques, and exploring therapeutic interventions to improve understanding and treatment of DPHLS. Conducting prospective cohort studies and developing biomarkers for early diagnosis and monitoring will be essential to advance patient care.

Diffusion tensor imaging in cerebral small vessel disease applications: opportunities and challenges.

Cerebral small vessel disease (CSVD) is a syndrome of pathology, imaging, and clinical manifestations caused primarily by a variety of functional or structural lesions in the small blood vessels of the brain. CSVD contributes to approximately 45% of dementia and 25% of ischemic strokes worldwide and is one of the most important causes of disability. The disease progresses insidiously, and patients often have no typical symptoms in the early stages, but have an increased risk of stroke, death, and poor long-term prognosis. Therefore, early diagnosis of CSVD is particularly important. Neuroimaging is the most important diagnostic tool used for CSVD. Therefore, it is important to explore the imaging mechanisms of CSVD for its early diagnosis and precise treatment. In this article, we review the principles and analysis methods of DTI, analyze the latest DTI studies on CSVD, clarify the disease-lesion mapping relationships between cerebral white matter (WM) microstructural damage and CSVD, explore the pathogenic mechanisms and preclinical imaging features of CSVD, and summarize the latest research directions of CSVD and research methods to provide a comprehensive and objective imaging basis for the diagnosis and treatment of CSVD.

6813 Des-Ciclesonide: A Novel Selective Glucocorticoid Receptor Modulator With Therapeutic Potential for Bronchopulmonary Dysplasia, a Chronic Lung Disease of Prematurity

Abstract Disclosure: N. El Khoury: None. J. Jaumotte: None. C. Min: None. C. Madigan: None. J. Wang: None. U. Chandran: None. V. Sampath: None. T.J. Cole: None. P. Monaghan-Nichols: None. R. Houtman: None. K.W. Nettles: None. D.B. DeFranco: None. Infants born before 30 weeks gestation are at risk of developing bronchopulmonary dysplasia (BPD), a prevalent chronic lung disease of prematurity. Glucocorticoids (GCs) such as dexamethasone (DEX) have been a mainstay of BPD prevention as they reduce lung inflammation and injury. However, their use is encumbered with several adverse effects including hyperglycemia, impaired somatic and brain growth and cerebral palsy. These major concerns have resulted in the AAP recommending caution in GC use in preterm infants.Ciclesonide (CIC), an inhaled GC prodrug approved for the treatment of asthma and allergic rhinitis in children, is converted to the potent glucocorticoid receptor (GR) agonist des-ciclesonide (DES) by enzymes enriched in the airways. We previously reported that s.c. delivery of CIC in neonatal rats activated GR transcriptional responses in lung but did not trigger the adverse effects on somatic growth, brain weight or cerebral white matter loss caused by DEX leading us to propose CIC as a potential new pharmacotherapy for BPD. To determine whether limited systemic metabolism of CIC in neonatal rats was solely responsible for its enhanced safety profile, we assessed various outcomes in neonatal rats followed s.c. delivery of its active metabolite DES. Consistent with previous studies, five daily s.c. injections of DEX led to a reduction in body and brain weight as well as reduced serum levels of insulin-like growth factor-1 and chronic hyperglycemia. Surprisingly, analogous s.c. injection of neonatal rats with DES, which has a higher binding affinity for GR than DEX, did not trigger any of these adverse effects. However, DES is as effective as DEX in reducing the expression of various proinflammatory cytokine mRNAs in neonatal rat lung induced by an 11-day systemic treatment with bleomycin. Bulk RNAseq analyses revealed transcriptional responses of neonatal lung and liver to DES, although less robust than that observed to DEX (i.e., 25% and 13% in lung and liver, respectively). Nonetheless, a NAPing assay for coregulator peptide binding showed increased binding of all the DES responsive peptide interactions relative to DEX and cortisol. All-atom molecular dynamics simulations revealed site-specific H-bonding changes within the GR ligand binding domain (LBD) caused by the bulky C16/C17substitution within DES, which was translated into broader changes in LBD structure, specifically revealed as differences in RMSF in helix 7/8 and the surfaces interacting with the NCOA2 peptide. Furthermore, network pathway analysis illustrated that DES mobility at helix 7/8 uniquely generated a meaningful allosteric signaling pathway between Q642 and NCOA2 peptide. In conclusion, the pharmacokinetic properties of the GR prodrug CIC coupled with the tissue-selective pharmacodynamic properties of its active metabolite DES make this FDA approved drug a potential new therapeutic agent for BPD. Presentation: 6/3/2024

Utility of cerebrovascular imaging biomarkers to detect cerebral amyloidosis.

The relationship between cerebrovascular disease (CVD) and amyloid beta (Aβ) in Alzheimer's disease (AD) is understudied. We hypothesized that magnetic resonance imaging (MRI)-based CVD biomarkers-including cerebral microbleeds (CMBs), lacunar infarction, and white matter hyperintensities (WMHs)-would correlate with Aβ positivity on positron emission tomography (Aβ-PET). We cross-sectionally analyzed data from the Alzheimer's Disease Neuroimaging Initiative (ADNI, N=1352). Logistic regression was used to calculate odds ratios (ORs), with Aβ-PET positivity as the standard-of-truth. Following adjustment, WMHs (OR=1.25) and superficial CMBs (OR=1.45) remained positively associated with Aβ-PET positivity (p<0.001). Deep CMBs and lacunes exhibited a varied relationship with Aβ-PET in cognitive subgroups. The combined diagnostic model, which included CVD biomarkers and other accessible measures, significantly predicted Aβ-PET (pseudo-R2=0.41). The study highlights the translational value of CVD biomarkers in diagnosing AD, and underscores the need for more research on their inclusion in diagnostic criteria. gov: ADNI-2 (NCT01231971), ADNI-3 (NCT02854033). Cerebrovascular biomarkers linked to amyloid beta (Aβ) in Alzheimer's disease (AD). White matter hyperintensities and cerebral microbleeds reliably predict Aβ-PET positivity. Relationships with Aβ-PET vary by cognitive stage. Novel accessible model predicts Aβ-PET status. Study supports multimodal diagnostic approaches.

Brain Magnetic Resonance Imaging Responses to Nonhypoxic Hypobaric Decompression

INTRODUCTION: The pathophysiological basis of neurological decompression sickness and the association between cerebral subcortical white matter (WM) change and nonhypoxic hypobaria remain poorly understood. Recent study of altitude decompression sickness risk evaluated acute WM responses to intensive hypobaric exposure using brain magnetic resonance imaging. METHODS: Six healthy men (20 to 50 yr) completed 6 h of hyperoxic hypobaria during three same-day altitude chamber decompressions to pressure altitudes ≥ 22,000 ft (6706 m). Research magnetic resonance imaging sequences, conducted on the days preceding and following decompression, evaluated subcortical WM integrity, cerebral blood flow, neuronal integrity (fractional anisotropy), and neurometabolite concentrations. RESULTS: No subcortical lesions were evident on diffusion weighted imaging and WM fractional anisotropy was unaffected. Mean WM blood flow was upregulated by 20% to over 25 mL · 100 g−1 · min−1. Gray matter flow was unchanged. There were no changes in gray matter or cerebellar neurometabolites. In parietal subcortical WM, levels of γ-aminobutyric acid (GABA) fell from (mean ± SD) 1.68 ± 0.2 to 1.35 ± 0.3 institutional units while glutathione (GSH) fell from 1.71 ± 0.4 to 1.25 ± 0.3 institutional units. Lactate increased postexposure in five subjects. CONCLUSIONS: Postexposure decrements in GABA and GSH imply WM insult with loss of neuroprotection and oxidative stress. An association between decrements in GABA and GSH support a common origin, while GSH decrements also correlate with WM blood flow responses. WM lactate increments are prone to error but suggest dysregulation of subcortical microvascular flow. WM neurometabolite and blood flow indices did not normalize by 24 h postexposure. Connolly D, Davagnanam I, Wylezinska-Arridge M, Mallon D, Wastling S, Lee VM. Brain magnetic resonance imaging responses to nonhypoxic hypobaric decompression. Aerosp Med Hum Perform. 2024; 95(10):733–740.