Astroglial calcium signaling and homeostasis in tuberous sclerosis complex.

Tuberous Sclerosis Complex (TSC) is a multisystem genetic disorder characterized by the development of benign tumors in various organs, including the brain, and is often accompanied by epilepsy, neurodevelopmental comorbidities including intellectual disability and autism. A key hallmark of TSC is the hyperactivation of the mechanistic target of rapamycin (mTOR) signaling pathway, which induces alterations in cortical development and metabolic processes in astrocytes, among other cellular functions. These changes could modulate seizure susceptibility, contributing to the progression of epilepsy and its associated comorbidities. Epilepsy is characterized by dysregulation of calcium (Ca2+) channels and intracellular Ca2+ dynamics. These factors contribute to hyperexcitability, disrupted synaptogenesis, and altered synchronization of neuronal networks, all of which contribute to seizure activity. This study investigates the intricate interplay between altered Ca2+ dynamics, mTOR pathway dysregulation, and cellular metabolism in astrocytes. The transcriptional profile of TSC patients revealed significant alterations in pathways associated with cellular respiration, ER and mitochondria, and Ca2+ regulation. TSC astrocytes exhibited lack of responsiveness to various stimuli, compromised oxygen consumption rate and reserve respiratory capacity underscoring their reduced capacity to react to environmental changes or cellular stress. Furthermore, our study revealed significant reduction of store operated calcium entry (SOCE) along with strong decrease of basal mitochondrial Ca2+ concentration and Ca2+ influx in TSC astrocytes. In addition, we observed alteration in mitochondrial membrane potential, characterized by increased depolarization in TSC astrocytes. Lastly, we provide initial evidence of structural abnormalities in mitochondria within TSC patient-derived astrocytes, suggesting a potential link between disrupted Ca2+ signaling and mitochondrial dysfunction. Our findings underscore the complexity of the relationship between Ca2+ signaling, mitochondria dynamics, apoptosis, and mTOR hyperactivation. Further exploration is required to shed light on the pathophysiology of TSC and on TSC associated neuropsychiatric disorders offering further potential avenues for therapeutic development.

Impaired GABAergic regulation and developmental immaturity in interneurons derived from the medial ganglionic eminence in the tuberous sclerosis complex.

GABAergic interneurons play a critical role in maintaining neural circuit balance, excitation-inhibition regulation, and cognitive function modulation. In tuberous sclerosis complex (TSC), GABAergic neuron dysfunction contributes to disrupted network activity and associated neurological symptoms, assumingly in a cell type-specific manner. This GABAergic centric study focuses on identifying specific interneuron subpopulations within TSC, emphasizing the unique characteristics of medial ganglionic eminence (MGE)- and caudal ganglionic eminence (CGE)-derived interneurons. Using single-nuclei RNA sequencing in TSC patient material, we identify somatostatin-expressing (SST+) interneurons as a unique and immature subpopulation in TSC. The disrupted maturation of SST+ interneurons may undergo an incomplete switch from excitatory to inhibitory GABAergic signaling during development, resulting in reduced inhibitory properties. Notably, this study reveals markers of immaturity specifically in SST+ interneurons, including an abnormal NKCC1/KCC2 ratio, indicating an imbalance in chloride homeostasis crucial for the postsynaptic consequences of GABAergic signaling as well as the downregulation of GABAA receptor subunits, GABRA1, and upregulation of GABRA2. Further exploration of SST+ interneurons revealed altered localization patterns of SST+ interneurons in TSC brain tissue, concentrated in deeper cortical layers, possibly linked to cortical dyslamination. In the epilepsy context, our research underscores the diverse cell type-specific roles of GABAergic interneurons in shaping seizures, advocating for precise therapeutic considerations. Moreover, this study illuminates the potential contribution of SST+ interneurons to TSC pathophysiology, offering insights for targeted therapeutic interventions.

Selective vulnerability of brainstem and cervical spinal cord regions in people with non-progressive multiple sclerosis of Black or African American and European ancestry.

BACKGROUND: We evaluated imaging features suggestive of neurodegeneration within the brainstem and upper cervical spinal cord (UCSC) in non-progressive multiple sclerosis (MS). METHODS: Standardized 3-Tesla three-dimensional brain magnetic resonance imaging (MRI) studies were prospectively acquired. Rates of change in volume, surface texture, curvature were quantified at the pons and medulla-UCSC. Whole and regional brain volumes and T2-weighted lesion volumes were also quantified. Independent regression models were constructed to evaluate differences between those of Black or African ancestry (B/AA) and European ancestry (EA) with non-progressive MS. RESULTS: 209 people with MS (pwMS) having at least two MRI studies, 29% possessing 3-6 timepoints, resulted in 487 scans for analysis. Median follow-up time between MRI timepoints was 1.33 (25th-75th percentile: 0.51-1.98) years. Of 183 non-progressive pwMS, 88 and 95 self-reported being B/AA and EA, respectively. Non-progressive pwMS demonstrated greater rates of decline in pontine volume (p < 0.0001) in B/AA and in medulla-UCSC volume (p < 0.0001) for EA pwMS. Longitudinal surface texture and curvature changes suggesting reduced tissue integrity were observed at the ventral medulla-UCSC (p < 0.001), dorsal pons (p < 0.0001) and dorsal medulla (p < 0.0001) but not the ventral pons (p = 0.92) between groups. CONCLUSIONS: Selectively vulnerable regions within the brainstem-UCSC may allow for more personalized approaches to disease surveillance and management.

MicroRNA-34a activation in tuberous sclerosis complex during early brain development may lead to impaired corticogenesis.

AIMS: Tuberous sclerosis complex (TSC) is a genetic disorder associated with dysregulation of the mechanistic target of rapamycin complex 1 (mTORC1) signalling pathway. Neurodevelopmental disorders, frequently present in TSC, are linked to cortical tubers in the brain. We previously reported microRNA-34a (miR-34a) among the most upregulated miRs in tubers. Here, we characterised miR-34a expression in tubers with the focus on the early brain development and assessed the regulation of mTORC1 pathway and corticogenesis by miR-34a. METHODS: We analysed the expression of miR-34a in resected cortical tubers (n = 37) compared with autopsy-derived control tissue (n = 27). The effect of miR-34a overexpression on corticogenesis was assessed in mice at E18. The regulation of the mTORC1 pathway and the expression of the bioinformatically predicted target genes were assessed in primary astrocyte cultures from three patients with TSC and in SH-SY5Y cells following miR-34a transfection. RESULTS: The peak of miR-34a overexpression in tubers was observed during infancy, concomitant with the presence of pathological markers, particularly in giant cells and dysmorphic neurons. miR-34a was also strongly expressed in foetal TSC cortex. Overexpression of miR-34a in mouse embryos decreased the percentage of cells migrated to the cortical plate. The transfection of miR-34a mimic in TSC astrocytes negatively regulated mTORC1 and decreased the expression of the target genes RAS related (RRAS) and NOTCH1. CONCLUSIONS: MicroRNA-34a is most highly overexpressed in tubers during foetal and early postnatal brain development. miR-34a can negatively regulate mTORC1; however, it may also contribute to abnormal corticogenesis in TSC.

Seizure-mediated iron accumulation and dysregulated iron metabolism after status epilepticus and in temporal lobe epilepsy.

Neuronal dysfunction due to iron accumulation in conjunction with reactive oxygen species (ROS) could represent an important, yet underappreciated, component of the epileptogenic process. However, to date, alterations in iron metabolism in the epileptogenic brain have not been addressed in detail. Iron-related neuropathology and antioxidant metabolic processes were investigated in resected brain tissue from patients with temporal lobe epilepsy and hippocampal sclerosis (TLE-HS), post-mortem brain tissue from patients who died after status epilepticus (SE) as well as brain tissue from the electrically induced SE rat model of TLE. Magnetic susceptibility of the presumed seizure-onset zone from three patients with focal epilepsy was compared during and after seizure activity. Finally, the cellular effects of iron overload were studied in vitro using an acute mouse hippocampal slice preparation and cultured human fetal astrocytes. While iron-accumulating neurons had a pyknotic morphology, astrocytes appeared to acquire iron-sequestrating capacity as indicated by prominent ferritin expression and iron retention in the hippocampus of patients with SE or TLE. Interictal to postictal comparison revealed increased magnetic susceptibility in the seizure-onset zone of epilepsy patients. Post-SE rats had consistently higher hippocampal iron levels during the acute and chronic phase (when spontaneous recurrent seizures are evident). In vitro, in acute slices that were exposed to iron, neurons readily took up iron, which was exacerbated by induced epileptiform activity. Human astrocyte cultures challenged with iron and ROS increased their antioxidant and iron-binding capacity, but simultaneously developed a pro-inflammatory phenotype upon chronic exposure. These data suggest that seizure-mediated, chronic neuronal iron uptake might play a role in neuronal dysfunction/loss in TLE-HS. On the other hand, astrocytes sequester iron, specifically in chronic epilepsy. This function might transform astrocytes into a highly resistant, pro-inflammatory phenotype potentially contributing to pro-epileptogenic inflammatory processes.

Histology and computed tomography of incidental calcifications in the human basal ganglia.

Incidental basal ganglia calcifications are a common finding on computed tomography (CT). We investigated the histological characteristics of these calcifications and their association with CT findings, using post-mortem basal ganglia tissue from 22 patients. Eight patients had basal ganglia calcifications on histology, and six patients had calcifications on CT, varying from mild to severe. Four patients had calcifications identified by both histology and CT, and two patients had calcifications detected by CT but not by histology, possibly because of insufficient tissue available. Calcifications were found mainly in the tunica media of arterioles located in the globus pallidus, which suggests that incidental CT calcifications are vascular in nature. However, tunica media calcifications, and thereby incidental basal ganglia calcifications, are probably not related to atherosclerosis.

COVID-19 in people with multiple sclerosis: A global data sharing initiative.

BACKGROUND: We need high-quality data to assess the determinants for COVID-19 severity in people with MS (PwMS). Several studies have recently emerged but there is great benefit in aligning data collection efforts at a global scale. OBJECTIVES: Our mission is to scale-up COVID-19 data collection efforts and provide the MS community with data-driven insights as soon as possible. METHODS: Numerous stakeholders were brought together. Small dedicated interdisciplinary task forces were created to speed-up the formulation of the study design and work plan. First step was to agree upon a COVID-19 MS core data set. Second, we worked on providing a user-friendly and rapid pipeline to share COVID-19 data at a global scale. RESULTS: The COVID-19 MS core data set was agreed within 48 hours. To date, 23 data collection partners are involved and the first data imports have been performed successfully. Data processing and analysis is an on-going process. CONCLUSIONS: We reached a consensus on a core data set and established data sharing processes with multiple partners to address an urgent need for information to guide clinical practice. First results show that partners are motivated to share data to attain the ultimate joint goal: better understand the effect of COVID-19 in PwMS.

The association between MRI brain volumes and computerized cognitive scores of people with multiple sclerosis.

BACKGROUND: Computerized cognitive assessment facilitates the incorporation of multi-domain cognitive monitoring into routine clinical care. The predictive validity of computerized cognitive assessment among people with multiple sclerosis (PwMS) has scarcely been investigated. OBJECTIVE: To explore the associations between brain volumes and cognitive scores from a computerized cognitive assessment battery (CAB, NeuroTrax) among PwMS. METHODS: PwMS were evaluated with the CAB and underwent brain MRI within 40 days. Cognitive assessment yielded age- and education-adjusted scores in 9 cognitive domains: memory, executive function, attention, information processing speed, visual spatial, verbal function, motor skills, problem solving, and working memory. The global cognitive score (GCS) is the average of all domain scores. MRI brain and lesion volumes were assessed with icobrain ms, a fully automated tissue and lesion segmentation and quantification software. RESULTS: 91 PwMS were included [Age: 52.1 ± 11.7 years, 64 (70%) female, EDSS: 3.4 ± 2.0, 79 (87%) with a relapsing remitting course]. Significant correlations were found between the GCS and whole brain, white matter, grey matter, thalamic, lateral ventricles, hippocampal and lesion volumes (Correlation coefficients: 0.46, 0.40, 0.25, 0.42, -0.36, 0.21, -0.3, respectively). Regression analysis revealed that lateral ventricles and thalamic volumes were the most consistent predictors of all cognitive domain scores. CONCLUSION: Computerized cognitive scores were significantly associated with quantified MRI. These findings support the predictive validity of multi-domain computerized cognitive assessment for people with multiple sclerosis.

miR147b: A novel key regulator of interleukin 1 beta-mediated inflammation in human astrocytes.

Astrocytes are important mediators of inflammatory processes in the brain and seem to play an important role in several neurological disorders, including epilepsy. Recent studies show that astrocytes produce several microRNAs, which may function as crucial regulators of inflammatory pathways and could be used as therapeutic target. We aim to study which miRNAs are produced by astrocytes during IL-1ß mediated inflammatory conditions in vitro, as well as their functional role and to validate these findings in human epileptogenic brain tissue. Sequencing was used to assess miRNA and mRNA expression in IL-1ß-stimulated human fetal astrocyte cultures. miRNAs were overexpressed in cell cultures using miRNA mimics. Expression of miRNAs in resected brain tissue from patients with tuberous sclerosis complex or temporal lobe epilepsy with hippocampal sclerosis was examined using in situ hybridization. Two differentially expressed miRNAs were found: miR146a and miR147b, which were associated with increased expression of genes related to the immune/inflammatory response. As previously reported for miR146a, overexpression of miR147b reduced the expression of the pro-inflammatory mediators IL-6 and COX-2 after IL-1ß stimulation in both astrocyte and tuberous sclerosis complex cell cultures. miR146a and miR147b overexpression decreased proliferation of astrocytes and promoted neuronal differentiation of human neural stem cells. Similarly to previous evidence for miR146a, miR147b was increased expressed in astrocytes in epileptogenic brain. Due to their anti-inflammatory effects, ability to restore aberrant astrocytic proliferation and promote neuronal differentiation, miR146a and miR147b deserve further investigation as potential therapeutic targets in neurological disorders associated with inflammation, such as epilepsy.

Measurement of Whole-Brain and Gray Matter Atrophy in Multiple Sclerosis: Assessment with MR Imaging.

Purpose To compare available methods for whole-brain and gray matter (GM) atrophy estimation in multiple sclerosis (MS) in terms of repeatability (same magnetic resonance [MR] imaging unit) and reproducibility (different system/field strength) for their potential clinical applications. Materials and Methods The softwares ANTs-v1.9, CIVET-v2.1, FSL-SIENAX/SIENA-5.0.1, Icometrix-MSmetrix-1.7, and SPM-v12 were compared. This retrospective study, performed between March 2015 and March 2017, collected data from (a) eight simulated MR images and longitudinal data (2 weeks) from 10 healthy control subjects to assess the cross-sectional and longitudinal accuracy of atrophy measures, (b) test-retest MR images in 29 patients with MS acquired within the same day at different imaging unit field strengths/manufacturers to evaluate precision, and (c) longitudinal data (1 year) in 24 patients with MS for the agreement between methods. Tissue segmentation, image registration, and white matter (WM) lesion filling were also evaluated. Multiple paired t tests were used for comparisons. Results High values of accuracy (0.87-0.97) for whole-brain and GM volumes were found, with the lowest values for MSmetrix. ANTs showed the lowest mean error (0.02%) for whole-brain atrophy in healthy control subjects, with a coefficient of variation of 0.5%. SPM showed the smallest mean error (0.07%) and coefficient of variation (0.08%) for GM atrophy. Globally, good repeatability (P > .05) but poor reproducibility (P < .05) were found for all methods. WM lesion filling technique mainly affected ANTs, MSmetrix, and SPM results (P < .05). Conclusion From this comparison, it would be possible to select a software for atrophy measurement, depending on the requirements of the application (research center, clinical trial) and its goal (accuracy and repeatability or reproducibility). An improved reproducibility is required for clinical application. © RSNA, 2018 Online supplemental material is available for this article.

Neuroinflammation and its relationship to changes in brain volume and white matter lesions in multiple sclerosis.

Brain magnetic resonance imaging is an important tool in the diagnosis and monitoring of multiple sclerosis patients. However, magnetic resonance imaging alone provides limited information for predicting an individual patient's disability progression. In part, this is because magnetic resonance imaging lacks sensitivity and specificity for detecting chronic diffuse and multi-focal inflammation mediated by activated microglia/macrophages. The aim of this study was to test for an association between 18 kDa translocator protein brain positron emission tomography signal, which arises largely from microglial activation, and measures of subsequent disease progression in multiple sclerosis patients. Twenty-one patients with multiple sclerosis (seven with secondary progressive disease and 14 with a relapsing remitting disease course) underwent T1- and T2-weighted and magnetization transfer magnetic resonance imaging at baseline and after 1 year. Positron emission tomography scanning with the translocator protein radioligand 11C-PBR28 was performed at baseline. Brain tissue and lesion volumes were segmented from the T1- and T2-weighted magnetic resonance imaging and relative 11C-PBR28 uptake in the normal-appearing white matter was estimated as a distribution volume ratio with respect to a caudate pseudo-reference region. Normal-appearing white matter distribution volume ratio at baseline was correlated with enlarging T2-hyperintense lesion volumes over the subsequent year (ρ = 0.59, P = 0.01). A post hoc analysis showed that this association reflected behaviour in the subgroup of relapsing remitting patients (ρ = 0.74, P = 0.008). By contrast, in the subgroup of secondary progressive patients, microglial activation at baseline was correlated with later progression of brain atrophy (ρ = 0.86, P = 0.04). A regression model including the baseline normal-appearing white matter distribution volume ratio, T2 lesion volume and normal-appearing white matter magnetization transfer ratio for all of the patients combined explained over 90% of the variance in enlarging lesion volume over the subsequent 1 year. Glial activation in white matter assessed by translocator protein PET significantly improves predictions of white matter lesion enlargement in relapsing remitting patients and is associated with greater brain atrophy in secondary progressive disease over a period of short term follow-up.

Predominance of Nonatherosclerotic Internal Elastic Lamina Calcification in the Intracranial Internal Carotid Artery.

BACKGROUND AND PURPOSE: Calcification of the intracranial internal carotid artery (iICA) is an independent risk factor for stroke. These calcifications are generally seen as manifestation of atherosclerosis, but histological investigations are limited. The aim of this study is to determine whether calcifications in the iICA are present in atherosclerotic plaques, or in other parts of the arterial wall. METHODS: Thirty-nine iICAs were histologically assessed, using digital microscopy to quantify the amount of calcification in the different layers of the arterial wall. RESULTS: Calcifications were found in the intima, around the internal elastic lamina and in the medial layer of the arterial wall. In 71% of the arteries, internal elastic lamina calcification contributed most to the total calcified cross-sectional surface area. Internal elastic lamina calcification was unrelated to the occurrence of atherosclerotic intimal lesions. Intimal calcifications were most often associated with atherosclerotic lesions, but also many noncalcified atherosclerotic lesions were found. CONCLUSIONS: In the iICA, calcifications are predominantly present around the internal elastic lamina, suggesting that this nonatherosclerotic type of calcification contributes to the previously observed increased risk of stroke in patients with iICA calcifications.

Track orientation density imaging (TODI) and track orientation distribution (TOD) based tractography.

Ever since the introduction of the concept of fiber tractography, methods to generate better and more plausible tractograms have become available. Many modern methods can handle complex fiber architecture and take on a probabilistic approach to account for different sources of uncertainty. The resulting tractogram from any such method typically represents a finite random sample from a complex distribution of possible tracks. Generating a higher amount of tracks allows for a more accurate depiction of the underlying distribution. The recently proposed method of track-density imaging (TDI) allows to capture the spatial distribution of a tractogram. In this work, we propose an extension of TDI towards the 5D spatio-angular domain, which we name track orientation density imaging (TODI). The proposed method aims to capture the full track orientation distribution (TOD). Just as the TDI map, the TOD is amenable to spatial super-resolution (or even sub-resolution), but in addition also to angular super-resolution. Through experiments on in vivo human subject data, an in silico numerical phantom and a challenging tractography phantom, we found that the TOD presents an increased amount of regional spatio-angular consistency, as compared to the fiber orientation distribution (FOD) from constrained spherical deconvolution (CSD). Furthermore, we explain how the amplitude of the TOD of a short-tracks distribution (i.e. where the track length is limited) can be interpreted as a measure of track-like local support (TLS). This in turn motivated us to explore the idea of TOD-based fiber tractography. In such a setting, the short-tracks TOD is able to guide a track along directions that are more likely to correspond to continuous structure over a longer distance. This powerful concept is shown to greatly robustify targeted as well as whole-brain tractography. We conclude that the TOD is a versatile tool that can be cast in many different roles and scenarios in the expanding domain of fiber tractography based methods and their applications.

Evaluating the effect of dimethyl fumarate on subclinical biomarkers in a real-world patient cohort.

OBJECTIVE: Evaluate the real-world effect of dimethyl fumarate (DMF) on subclinical biomarkers in patients with relapsing-remitting multiple sclerosis (RRMS) and compare with results from clinical trials. METHODS: Magnetic resonance imaging (MRI) data from 102 RRMS patients were retrospectively collected and processed using icobrain to assess brain atrophy and to assist semi-manual lesion count. RESULTS: Mean (±SD) annualized percent brain volume change in the first 3 years after DMF-initiation were: -0.33 ± 0.68, -0.10 ± 0.60, and - 0.35 ± 0.71%/year, respectively. No new FLAIR lesions were detected in 73.7%, 77.3%, and 73.3% of the patients during years 1, 2, and 3. CONCLUSIONS: Results of this real-world study were consistent with previous DMF phase III clinical trials, supporting the generalizability of the effects observed in clinical trials to the real-world clinical setting.

RT-PCR assay to detect FGFR3::TACC3 fusions in formalin-fixed, paraffin-embedded glioblastoma samples.

Background: One targeted treatment option for isocitrate dehydrogenase (IDH)-wild-type glioblastoma focuses on tumors with fibroblast growth factor receptor 3::transforming acidic coiled-coil-containing protein 3 (FGFR3::TACC3) fusions. FGFR3::TACC3 fusion detection can be challenging, as targeted RNA next-generation sequencing (NGS) is not routinely performed, and immunohistochemistry is an imperfect surrogate marker. Fusion status can be determined using reverse transcription polymerase chain reaction (RT-PCR) on fresh frozen (FF) material, but sometimes only formalin-fixed, paraffin-embedded (FFPE) tissue is available. Aim: To develop an RT-PCR assay to determine FGFR3::TACC3 status in FFPE glioblastoma samples. Methods: Twelve tissue microarrays with 353 historical glioblastoma samples were immunohistochemically stained for FGFR3. Samples with overexpression of FGFR3 (n = 13) were subjected to FGFR3::TACC3 RT-PCR on FFPE, using 5 primer sets for the detection of 5 common fusion variants. Fusion-negative samples were additionally analyzed with NGS (n = 6), FGFR3 Fluorescence In Situ Hybridization (n = 6), and RNA sequencing (n = 5). Results: Using RT-PCR on FFPE material of the 13 samples with FGFR3 overexpression, we detected an FGFR3::TACC3 fusion in 7 samples, covering 3 different fusion variants. For 5 of these FF was available, and the presence of the fusion was confirmed through RT-PCR on FF. With RNA sequencing, 1 additional sample was found to harbor an FGFR3::TACC3 fusion (variant not covered by current RT-PCR for FFPE). The frequency of FGFR3::TACC3 fusion in this cohort was 9/353 (2.5%). Conclusions: RT-PCR for FGFR3::TACC3 fusions can successfully be performed on FFPE material, with a specificity of 100% and (due to limited primer sets) a sensitivity of 83.3%. This assay allows for the identification of potential targeted treatment options when only formalin-fixed tissue is available.

Artificial Intelligence Assistive Software Tool for Automated Detection and Quantification of Amyloid-Related Imaging Abnormalities.

Importance: Amyloid-related imaging abnormalities (ARIA) are brain magnetic resonance imaging (MRI) findings associated with the use of amyloid-ß-directed monoclonal antibody therapies in Alzheimer disease (AD). ARIA monitoring is important to inform treatment dosing decisions and might be improved through assistive software. Objective: To assess the clinical performance of an artificial intelligence (AI)-based software tool for assisting radiological interpretation of brain MRI scans in patients monitored for ARIA. Design, Setting, and Participants: This diagnostic study used a multiple-reader multiple-case design to evaluate the diagnostic performance of radiologists assisted by the software vs unassisted. The study enrolled 16 US Board of Radiology-certified radiologists to perform radiological reading with (assisted) and without the software (unassisted). The study encompassed 199 retrospective cases, where each case consisted of a predosing baseline and a postdosing follow-up MRI of patients from aducanumab clinical trials PRIME, EMERGE, and ENGAGE. Statistical analysis was performed from April to July 2023. Exposures: Use of icobrain aria, an AI-based assistive software for ARIA detection and quantification. Main Outcomes and Measures: Coprimary end points were the difference in diagnostic accuracy between assisted and unassisted detection of ARIA-E (edema and/or sulcal effusion) and ARIA-H (microhemorrhage and/or superficial siderosis) independently, assessed with the area under the receiver operating characteristic curve (AUC). Results: Among the 199 participants included in this study of radiological reading performance, mean (SD) age was 70.4 (7.2) years; 105 (52.8%) were female; 23 (11.6%) were Asian, 1 (0.5%) was Black, 157 (78.9%) were White, and 18 (9.0%) were other or unreported race and ethnicity. Among the 16 radiological readers included, 2 were specialized neuroradiologists (12.5%), 11 were male individuals (68.8%), 7 were individuals working in academic hospitals (43.8%), and they had a mean (SD) of 9.5 (5.1) years of experience. Radiologists assisted by the software were significantly superior in detecting ARIA than unassisted radiologists, with a mean assisted AUC of 0.87 (95% CI, 0.84-0.91) for ARIA-E detection (AUC improvement of 0.05 [95% CI, 0.02-0.08]; P = .001]) and 0.83 (95% CI, 0.78-0.87) for ARIA-H detection (AUC improvement of 0.04 [95% CI, 0.02-0.07]; P = .001). Sensitivity was significantly higher in assisted reading compared with unassisted reading (87% vs 71% for ARIA-E detection; 79% vs 69% for ARIA-H detection), while specificity remained above 80% for the detection of both ARIA types. Conclusions and Relevance: This diagnostic study found that radiological reading performance for ARIA detection and diagnosis was significantly better when using the AI-based assistive software. Hence, the software has the potential to be a clinically important tool to improve safety monitoring and management of patients with AD treated with amyloid-ß-directed monoclonal antibody therapies.

Super-resolution for multislice diffusion tensor imaging.

Diffusion weighted magnetic resonance images are often acquired with single shot multislice imaging sequences, because of their short scanning times and robustness to motion. To minimize noise and acquisition time, images are generally acquired with either anisotropic or isotropic low resolution voxels, which impedes subsequent posterior image processing and visualization. In this article, we propose a super-resolution method for diffusion weighted imaging that combines anisotropic multislice images to enhance the spatial resolution of diffusion tensor data. Each diffusion weighted image is reconstructed from a set of arbitrarily oriented images with a low through-plane resolution. The quality of the reconstructed diffusion weighted images was evaluated by diffusion tensor metrics and tractography. Experiments with simulated data, a hardware DTI phantom, as well as in vivo human brain data were conducted. Our results show a significant increase in spatial resolution of the diffusion tensor data while preserving high signal to noise ratio.

Mastication dyspraxia: a neurodevelopmental disorder reflecting disruption of the cerebellocerebral network involved in planned actions.

This paper reports the longitudinal clinical, neurocognitive, and neuroradiological findings in an adolescent patient with nonprogressive motor and cognitive disturbances consistent with a diagnosis of developmental coordination disorder (DCD). In addition to prototypical DCD, the development of mastication was severely impaired, while no evidence of swallowing apraxia, dysphagia, sensorimotor disturbances, abnormal tone, or impaired general cognition was found. He suffered from bronchopulmonary dysplasia and was ventilated as a newborn for 1.5 months. At the age of 3 months, a ventriculoperitoneal shunt was surgically installed because of obstructive hydrocephalus secondary to perinatal intraventricular bleeding. At the age of 5 years, the patient's attempts to masticate were characterized by rough, effortful, and laborious biting movements confined to the vertical plane. Solid food particles had a tendency to get struck in his mouth and there was constant spillage. As a substitute for mastication, he moved the unground food with his fingers in a lateral direction to the mandibular and maxillary vestibule to externally manipulate and squeeze the food between cheek and teeth with the palm of his hand. Once the food was sufficiently soft, the bolus was correctly transported by the tongue in posterior direction and normal deglutition took place. Repeat magnetic resonance imaging (MRI) during follow-up disclosed mild structural abnormalities as the sequelae of the perinatal intraventricular bleeding, but this could not explain impaired mastication behavior. Quantified Tc-99m-ethylcysteinate dimer single-photon emission computed tomography (Tc-99m-ECD SPECT), however, revealed decreased perfusion in the left cerebellar hemisphere, as well as in both inferior lateral frontal regions, both motor cortices, and the right anterior and lateral temporal areas. Anatomoclinical findings in this patient with DCD not only indicate that the functional integrity of the cerebellocerebral network is crucially important in the planning and execution of skilled actions, but also seem to show for the first time that mastication deficits may be of true apraxic origin. As a result, it is hypothesized that "mastication dyspraxia" may have to be considered as a distinct nosological entity within the group of the developmental dyspraxias following a disruption of the cerebellocerebral network involved in planned actions.

White matter differences in euthymic bipolar I disorder: a combined magnetic resonance imaging and diffusion tensor imaging voxel-based study.

OBJECTIVES: A broad range of subtle and markedly heterogenous neuroanatomical abnormalities of grey matter and white matter have been reported in bipolar disorder. Euthymic bipolar disorder patients represent a clinically homogenous group in which to identify trait-based biomarkers of bipolar disorder. In this study, we sought to clarify the nature and extent of neuroanatomical differences in a large, clinically homogeneous group of euthymic bipolar disorder patients. METHODS: Structural magnetic resonance imaging (sMRI) was obtained for 60 patients with prospectively confirmed euthymic bipolar I disorder and 60 individually age- and gender-matched healthy volunteers. High angular resolution diffusion tensor imaging (DTI) scans were obtained for a subset of this sample comprising 35 patients and 43 controls. Voxel-based analysis of both sMRI and DTI data sets was performed. RESULTS: Bipolar disorder patients displayed global reductions in white matter volume and fractional anisotropy reductions in the corpus callosum, posterior cingulum, and prefrontal white matter compared with controls. There were corresponding increases in radial diffusivity in the callosal splenium in patients compared with controls. No significant group differences were detected in grey matter. In patients, lithium was associated with a bilateral increase in grey matter volume in the temporal lobes, but not with any DTI parameter. CONCLUSIONS: Euthymic bipolar I disorder is characterized by both diffuse global white matter deficits and potential regional disorganization in interhemispheric and longitudinal tracts, while grey matter appears to be preserved.