Brain aerobic glycolysis and resilience in Alzheimer disease.

The distribution of brain aerobic glycolysis (AG) in normal young adults correlates spatially with amyloid-beta (Aß) deposition in individuals with symptomatic and preclinical Alzheimer disease (AD). Brain AG decreases with age, but the functional significance of this decrease with regard to the development of AD symptomatology is poorly understood. Using PET measurements of regional blood flow, oxygen consumption, and glucose utilization-from which we derive AG-we find that cognitive impairment is strongly associated with loss of the typical youthful pattern of AG. In contrast, amyloid positivity without cognitive impairment was associated with preservation of youthful brain AG, which was even higher than that seen in cognitively unimpaired, amyloid negative adults. Similar findings were not seen for blood flow nor oxygen consumption. Finally, in cognitively unimpaired adults, white matter hyperintensity burden was found to be specifically associated with decreased youthful brain AG. Our results suggest that AG may have a role in the resilience and/or response to early stages of amyloid pathology and that age-related white matter disease may impair this process.

Accuracy of TrUE-Net in comparison to established white matter hyperintensity segmentation methods: An independent validation study.

White matter hyperintensities (WMH) are nearly ubiquitous in the aging brain, and their topography and overall burden are associated with cognitive decline. Given their numerosity, accurate methods to automatically segment WMH are needed. Recent developments, including the availability of challenge data sets and improved deep learning algorithms, have led to a new promising deep-learning based automated segmentation model called TrUE-Net, which has yet to undergo rigorous independent validation. Here, we compare TrUE-Net to six established automated WMH segmentation tools, including a semi-manual method. We evaluated the techniques at both global and regional level to compare their ability to detect the established relationship between WMH burden and age. We found that TrUE-Net was highly reliable at identifying WMH regions with low false positive rates, when compared to semi-manual segmentation as the reference standard. TrUE-Net performed similarly or favorably when compared to the other automated techniques. Moreover, TrUE-Net was able to detect relationships between WMH and age to a similar degree as the reference standard semi-manual segmentation at both the global and regional level. These results support the use of TrUE-Net for identifying WMH at the global or regional level, including in large, combined datasets.

MOG and AQP4 Antibodies among Children with Multiple Sclerosis and Controls.

OBJECTIVE: The purpose of this study was to determine the frequency of myelin oligodendrocyte glycoprotein (MOG)-IgG and aquaporin-4 (AQP4)-IgG among patients with pediatric-onset multiple sclerosis (POMS) and healthy controls, to determine whether seropositive cases fulfilled their respective diagnostic criteria, to compare characteristics and outcomes in children with POMS versus MOG-IgG-associated disease (MOGAD), and identify clinical features associated with final diagnosis. METHODS: Patients with POMS and healthy controls were enrolled at 14 US sites through a prospective case-control study on POMS risk factors. Serum AQP4-IgG and MOG-IgG were assessed using live cell-based assays. RESULTS: AQP4-IgG was negative among all 1,196 participants, 493 with POMS and 703 healthy controls. MOG-IgG was positive in 30 of 493 cases (6%) and zero controls. Twenty-five of 30 patients positive with MOG-IgG (83%) had MOGAD, whereas 5 of 30 (17%) maintained a diagnosis of multiple sclerosis (MS) on re-review of records. MOGAD cases were more commonly in female patients (21/25 [84%] vs 301/468 [64%]; p = 0.044), younger age (mean = 8.2 ± 4.2 vs 14.7 ± 2.6 years; p < 0.001), more commonly had initial optic nerve symptoms (16/25 [64%] vs 129/391 [33%]; p = 0.002), or acute disseminated encephalomyelitis (ADEM; 8/25 [32%] vs 9/468 [2%]; p < 0.001), and less commonly had initial spinal cord symptoms (3/20 [15%] vs 194/381 [51%]; p = 0.002), serum Epstein-Barr virus (EBV) positivity (11/25 [44%] vs 445/468 [95%]; p < 0.001), or cerebrospinal fluid oligoclonal bands (5/25 [20%] vs 243/352 [69%]; p < 0.001). INTERPRETATION: MOG-IgG and AQP4-IgG were not identified among healthy controls confirming their high specificity for pediatric central nervous system (CNS) demyelinating disease. Five percent of those with prior POMS diagnoses ultimately had MOGAD; and none had AQP4-IgG positivity. Clinical features associated with a final diagnosis of MOGAD in those with suspected MS included initial ADEM phenotype, younger age at disease onset, and lack of EBV exposure. ANN NEUROL 2023;93:271-284.

Automated analysis of low-field brain MRI in cerebral malaria.

A central challenge of medical imaging studies is to extract biomarkers that characterize disease pathology or outcomes. Modern automated approaches have found tremendous success in high-resolution, high-quality magnetic resonance images. These methods, however, may not translate to low-resolution images acquired on magnetic resonance imaging (MRI) scanners with lower magnetic field strength. In low-resource settings where low-field scanners are more common and there is a shortage of radiologists to manually interpret MRI scans, it is critical to develop automated methods that can augment or replace manual interpretation, while accommodating reduced image quality. We present a fully automated framework for translating radiological diagnostic criteria into image-based biomarkers, inspired by a project in which children with cerebral malaria (CM) were imaged using low-field 0.35 Tesla MRI. We integrate multiatlas label fusion, which leverages high-resolution images from another sample as prior spatial information, with parametric Gaussian hidden Markov models based on image intensities, to create a robust method for determining ventricular cerebrospinal fluid volume. We also propose normalized image intensity and texture measurements to determine the loss of gray-to-white matter tissue differentiation and sulcal effacement. These integrated biomarkers have excellent classification performance for determining severe brain swelling due to CM.

Mechanisms of Transcranial Doppler Ultrasound phenotypes in paediatric cerebral malaria remain elusive.

BACKGROUND: Cerebral malaria (CM) results in significant paediatric death and neurodisability in sub-Saharan Africa. Several different alterations to typical Transcranial Doppler Ultrasound (TCD) flow velocities and waveforms in CM have been described, but mechanistic contributors to these abnormalities are unknown. If identified, targeted, TCD-guided adjunctive therapy in CM may improve outcomes. METHODS: This was a prospective, observational study of children 6 months to 12 years with CM in Blantyre, Malawi recruited between January 2018 and June 2021. Medical history, physical examination, laboratory analysis, electroencephalogram, and magnetic resonance imaging were undertaken on presentation. Admission TCD results determined phenotypic grouping following a priori definitions. Evaluation of the relationship between haemodynamic, metabolic, or intracranial perturbations that lead to these observed phenotypes in other diseases was undertaken. Neurological outcomes at hospital discharge were evaluated using the Paediatric Cerebral Performance Categorization (PCPC) score. RESULTS: One hundred seventy-four patients were enrolled. Seven (4%) had a normal TCD examination, 57 (33%) met criteria for hyperaemia, 50 (29%) for low flow, 14 (8%) for microvascular obstruction, 11 (6%) for vasospasm, and 35 (20%) for isolated posterior circulation high flow. A lower cardiac index (CI) and higher systemic vascular resistive index (SVRI) were present in those with low flow than other groups (p < 0.003), though these values are normal for age (CI 4.4 [3.7,5] l/min/m2, SVRI 1552 [1197,1961] dscm-5m2). Other parameters were largely not significantly different between phenotypes. Overall, 118 children (68%) had a good neurological outcome. Twenty-three (13%) died, and 33 (19%) had neurological deficits. Outcomes were best for participants with hyperaemia and isolated posterior high flow (PCPC 1-2 in 77 and 89% respectively). Participants with low flow had the least likelihood of a good outcome (PCPC 1-2 in 42%) (p < 0.001). Cerebral autoregulation was significantly better in children with good outcome (transient hyperemic response ratio (THRR) 1.12 [1.04,1.2]) compared to a poor outcome (THRR 1.05 [0.98,1.02], p = 0.05). CONCLUSIONS: Common pathophysiological mechanisms leading to TCD phenotypes in non-malarial illness are not causative in children with CM. Alternative mechanistic contributors, including mechanical factors of the cerebrovasculature and biologically active regulators of vascular tone should be explored.

Performance of Automated RAPID Intracranial Hemorrhage Detection in Real-World Practice: A Single-Institution Experience.

BACKGROUND AND PURPOSE: Intracranial hemorrhage (ICH) is a common finding in patients presenting to the emergency department with acute neurological symptoms. Noncontrast head computed tomography (NCCT) is the primary modality for assessment and detection of ICH in the acute setting. RAPID ICH software aims to automatically detect ICH on NCCT and was previously shown to have high accuracy when applied to a curated test data set. Here, we measured the test performance characteristics of RAPID ICH software in detecting ICH on NCCT performed in patients undergoing emergency stroke evaluation at a tertiary academic comprehensive stroke center. MATERIALS AND METHODS: This retrospective study assessed consecutive patients over a 6-month period who presented with acute neurological symptoms suspicious for stroke and underwent NCCT with RAPID ICH postprocessing. RAPID ICH detection was compared with the interpretation of a reference standard comprising a board-certified or board-eligible neuroradiologist, or in cases of discrepancy, adjudicated by a consensus panel of 3 neuroradiologists. Accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of RAPID ICH for ICH detection were determined. RESULTS: Three hundred seven NCCT scans were included in the study. RAPID ICH correctly identified 34 of 37 cases with ICH and 228 of 270 without ICH. RAPID ICH had a sensitivity of 91.9% (78.1%-98.3%), specificity of 84.4% (79.6%-88.6%), NPV of 98.7% (96.3%-99.6%), PPV of 44.7% (37.6%-52.1%), and overall accuracy of 85.3% (80.9%-89.1%). CONCLUSIONS: In a real-world scenario, RAPID ICH software demonstrated high NPV but low PPV for the presence of ICH when evaluating possible stroke patients.

Persistent metabolic youth in the aging female brain.

Sex differences influence brain morphology and physiology during both development and aging. Here we apply a machine learning algorithm to a multiparametric brain PET imaging dataset acquired in a cohort of 20- to 82-year-old, cognitively normal adults (n = 205) to define their metabolic brain age. We find that throughout the adult life span the female brain has a persistently lower metabolic brain age-relative to their chronological age-compared with the male brain. The persistence of relatively younger metabolic brain age in females throughout adulthood suggests that development might in part influence sex differences in brain aging. Our results also demonstrate that trajectories of natural brain aging vary significantly among individuals and provide a method to measure this.

Pediatric Thrombectomy: Design and Workflow Lessons From Two Experienced Centers.

Endovascular thrombectomy has played a major role in advancing adult stroke care and may serve a similar role in pediatric stroke care. However, there is a need to develop better evidence and infrastructure for pediatric stroke care. In this work, we review 2 experienced pediatric endovascular thrombectomy programs and examine key design features in both care environments, including a formalized protocol and workflow, integration with an adult endovascular thrombectomy workflow, simplification and automation of workflow steps, pediatric adaptations of stroke imaging, advocacy of pediatric stroke care, and collaboration between providers, among others. These essential features transcend any single hospital environment and may provide an important foundation for other pediatric centers that aim to enhance the care of children with stroke.

Real-World Effectiveness of Initial Disease-Modifying Therapies in Pediatric Multiple Sclerosis.

OBJECTIVE: To assess real-world effectiveness of initial treatment with newer compared to injectable disease-modifying therapies (DMTs) on disease activity in pediatric multiple sclerosis (MS) and clinically isolated syndrome (CIS). METHODS: This is a cohort study of children with MS/CIS followed at 12 clinics in the US Network of Pediatric MS Centers, who received initial therapy with newer (fingolimod, dimethyl fumarate, teriflunomide, natalizumab, rituximab, ocrelizumab) or injectable (interferon-ß, glatiramer acetate) DMTs. Propensity scores (PSs) were computed, including preidentified confounders. Relapse rate while on initial DMT was modeled with negative binomial regression, adjusted for PS-quintile. Time to new/enlarging T2-hyperintense and gadolinium-enhancing lesions on brain magnetic resonance imaging were modeled with midpoint survival analyses, adjusted for PS-quintile. RESULTS: A total of 741 children began therapy before 18 years, 197 with newer and 544 with injectable DMTs. Those started on newer DMTs were older (15.2 vs injectable 14.4 years, p = 0.001) and less likely to have a monofocal presentation. In PS-quintile-adjusted analysis, those on newer DMTs had a lower relapse rate than those on injectables (rate ratio = 0.45, 95% confidence interval (CI) = 0.29-0.70, p < 0.001; rate difference = 0.27, 95% CI = 0.14-0.40, p = 0.004). One would need to treat with newer rather than injectable DMTs for 3.7 person-years to prevent 1 relapse. Those started on newer DMTs had a lower rate of new/enlarging T2 (hazard ratio [HR] = 0.51, 95% CI = 0.36-0.72, p < 0.001) and gadolinium-enhancing lesions (HR = 0.38, 95% CI = 0.23-0.63, p < 0.001) than those on injectables. INTERPRETATION: Initial treatment of pediatric MS/CIS with newer DMTs led to better disease activity control compared to injectables, supporting greater effectiveness of newer therapies. Long-term safety data for newer DMTs are required. ANN NEUROL 2020 ANN NEUROL 2020;88:42-55.

Improved relapse recovery in paediatric compared to adult multiple sclerosis.

Incomplete relapse recovery contributes to disability accrual and earlier onset of secondary progressive multiple sclerosis. We sought to investigate the effect of age on relapse recovery. We identified patients with multiple sclerosis from two longitudinal prospective studies, with an Expanded Disability Status Scale (EDSS) score within 30 days after onset of an attack, and follow-up EDSS 6 months after attack. Adult patients with multiple sclerosis (n = 632) were identified from the Comprehensive Longitudinal Investigations in Multiple Sclerosis at Brigham study (CLIMB), and paediatric patients (n = 132) from the US Network of Paediatric Multiple Sclerosis Centers (NPMSC) registry. Change in EDSS was defined as the difference in EDSS between attack and follow-up. Change in EDSS at follow-up compared to baseline was significantly lower in children compared to adults (P = 0.001), as were several functional system scores. Stratification by decade at onset for change in EDSS versus age found for every 10 years of age, EDSS recovery is reduced by 0.15 points (P < 0.0001). A larger proportion of children versus adults demonstrated improvement in EDSS following an attack (P = 0.006). For every 10 years of age, odds of EDSS not improving increase by 1.33 times (P < 0.0001). Younger age is associated with improved recovery from relapses. Age-related mechanisms may provide novel therapeutic targets for disability accrual in multiple sclerosis.

Genetically defined cellular correlates of the baseline brain MRI signal.

fMRI revolutionized neuroscience by allowing in vivo real-time detection of human brain activity. While the nature of the fMRI signal is understood as resulting from variations in the MRI signal due to brain-activity-induced changes in the blood oxygenation level (BOLD effect), these variations constitute a very minor part of a baseline MRI signal. Hence, the fundamental (and not addressed) questions are how underlying brain cellular composition defines this baseline MRI signal and how a baseline MRI signal relates to fMRI. Herein we investigate these questions by using a multimodality approach that includes quantitative gradient recalled echo (qGRE), volumetric and functional connectivity MRI, and gene expression data from the Allen Human Brain Atlas. We demonstrate that in vivo measurement of the major baseline component of a GRE signal decay rate parameter (R2t*) provides a unique genetic perspective into the cellular constituents of the human cortex and serves as a previously unidentified link between cortical tissue composition and fMRI signal. Data show that areas of the brain cortex characterized by higher R2t* have high neuronal density and have stronger functional connections to other brain areas. Interestingly, these areas have a relatively smaller concentration of synapses and glial cells, suggesting that myelinated cortical axons are likely key cortical structures that contribute to functional connectivity. Given these associations, R2t* is expected to be a useful signal in assessing microstructural changes in the human brain during development and aging in health and disease.

Brain Nutrition: A Life Span Approach.

Appraising success in meeting the world's nutritional needs has largely focused on infant mortality and anthropometric measurements with an emphasis on the first 1,000 days (conception to approximately age 2 years). This ignores the unique nutritional needs of the human brain. Although the intrauterine environment and the early postnatal years are important, equally critical periods follow during which the brain's intricate wiring is established for a lifetime of experience-driven remodeling. At the peak of this process during childhood, the human brain may account for 50% of the body's basal nutritional requirement. Thus, the consequences of proper nutritional management of the brain play out over a lifetime. Our motivation in preparing this review was to move the human brain into a more central position in the planning of nutritional programs. Here we review the macro- and micronutrient requirements of the human brain and how they are delivered, from conception to adulthood.

Progressive multifocal leukoencephalopathy treated with nivolumab.

Therapy for progressive multifocal leukoencephalopathy (PML) remains challenging since there are no antiviral therapies available for JC virus. Immune reconstitution has improved the prognosis in many settings where PML occurs, but it often is not possible in PML patients with hematologic malignancies. We describe the first biopsy proven PML case where the PD-1 inhibitor nivolumab appears to have stimulated immune activation resulting in effective control of PML in a patient with hematologic malignancy. This report supports further investigation of the utility of checkpoint inhibitors for treating PML where other immune reconstitution options are not available.

Glucose Requirements of the Developing Human Brain.

Adequate nutrition is critical for human brain development, which depends particularly upon glucose. The adult human brain accounts for 20% to 25% of total body resting glucose consumption, and studies indicate that the developing brain requires an even greater percentage of glucose. Here we critically review the currently available data on glucose requirements for early childhood brain development. Implications of these findings are then discussed in the context of childhood malnutrition and future areas of investigation.

Resting state signal latency predicts laterality in pediatric medically refractory temporal lobe epilepsy.

PURPOSE: Temporal lobe epilepsy (TLE) affects resting state brain networks in adults. This study aims to correlate resting state functional MRI (rsMRI) signal latency in pediatric TLE patients with their laterality. METHODS: From 2006 to 2016, 26 surgical TLE patients (12 left, 14 right) with a mean age of 10.7 years (range 0.9-18) were prospectively studied. Preoperative rsMRI was obtained in patients with concordant lateralizing structural MRI, EEG, and PET studies. Standard preprocessing techniques and seed-based rsMRI analyses were performed. Additionally, the latency in rsMRI signal between each 6 mm voxel sampled was examined, compared to the global mean signal, and projected onto standard atlas space for individuals and the cohort. RESULTS: All but one of the 26 patients improved seizure frequency postoperatively with a mean follow-up of 2.9 years (range 0-7.7), with 21 patients seizure-free. When grouped for epileptogenic laterality, the latency map qualitatively demonstrated that the right TLE patients had a relatively early signal pattern, whereas the left TLE patients had a relatively late signal pattern compared to the global mean signal in the right temporal lobe. Quantitatively, the two groups had significantly different signal latency clusters in the bilateral temporal lobes (p < 0.001). CONCLUSION: There are functional MR signal latency changes in medical refractory pediatric TLE patients. Qualitatively, signal latency in the right temporal lobe precedes the mean signal in right TLE patients and is delayed in left TLE patients. With larger confirmatory studies, preoperative rsMRI latency analysis may offer an inexpensive, noninvasive adjunct modality to lateralize pediatric TLE.

Feeding the brain and nurturing the mind: Linking nutrition and the gut microbiota to brain development.

The human gut contains a microbial community composed of tens of trillions of organisms that normally assemble during the first 2-3 y of postnatal life. We propose that brain development needs to be viewed in the context of the developmental biology of this "microbial organ" and its capacity to metabolize the various diets we consume. We hypothesize that the persistent cognitive abnormalities seen in children with undernutrition are related in part to their persistent gut microbiota immaturity and that specific regions of the brain that normally exhibit persistent juvenile (neotenous) patterns of gene expression, including those critically involved in various higher cognitive functions such as the brain's default mode network, may be particularly vulnerable to the effects of microbiota immaturity in undernourished children. Furthermore, we postulate that understanding the interrelationships between microbiota and brain metabolism in childhood undernutrition could provide insights about responses to injury seen in adults. We discuss approaches that can be used to test these hypotheses, their ramifications for optimizing nutritional recommendations that promote healthy brain development and function, and the potential societal implications of this area of investigation.