Neurological Disorders and Women's Health: Contribution of Molecular Neuroimaging Techniques.

Sex differences in brain physiology and the mechanisms of drug action have been extensively reported. These biological variances, from structure to hormonal and genetic aspects, can profoundly influence healthy functioning and disease mechanisms and might have implications for treatment and drug development. Molecular neuroimaging techniques may help to disclose sex's impact on brain functioning, as well as the neuropathological changes underpinning several diseases. This narrative review summarizes recent lines of evidence based on PET and SPECT imaging, highlighting sex differences in normal conditions and various neurological disorders.

Imaging of brain barrier inflammation and brain fluid drainage in human neurological diseases.

The intricate relationship between the central nervous system (CNS) and the immune system plays a crucial role in the pathogenesis of various neurological diseases. Understanding the interactions among the immunopathological processes at the brain borders is essential for advancing our knowledge of disease mechanisms and developing novel diagnostic and therapeutic approaches. In this review, we explore the emerging role of neuroimaging in providing valuable insights into brain barrier inflammation and brain fluid drainage in human neurological diseases. Neuroimaging techniques have enabled us not only to visualize and assess brain structures, but also to study the dynamics of the CNS in health and disease in vivo. By analyzing imaging findings, we can gain a deeper understanding of the immunopathology observed at the brain-immune interface barriers, which serve as critical gatekeepers that regulate immune cell trafficking, cytokine release, and clearance of waste products from the brain. This review explores the integration of neuroimaging data with immunopathological findings, providing valuable insights into brain barrier integrity and immune responses in neurological diseases. Such integration may lead to the development of novel diagnostic markers and targeted therapeutic approaches that can benefit patients with neurological disorders.

Live Mapping of the Brain Extracellular Matrix and Remodeling in Neurological Disorders.

Live imaging of the brain extracellular matrix (ECM) provides vital insights into changes that occur in neurological disorders. Current techniques such as second or third-harmonic generation offer limited contrast for live imaging of the brain ECM. Here, a new method, pan-ECM via chemical labeling of extracellular proteins, is introduced for live brain ECM imaging. pan-ECM labels all major ECM components in live tissue including the interstitial matrix, basement membrane, and perineuronal nets. pan-ECM enables in vivo observation of the ECM heterogeneity between the glioma core and margin, as well as the assessment of ECM deterioration under stroke condition, without ECM shrinkage from tissue fixation. These findings indicate that the pan-ECM approach is a novel way to image the entire brain ECM in live brain tissue with optical resolution. pan-ECM has the potential to advance the understanding of ECM in brain function and neurological diseases.

Enlarged Perivascular Space and Index for Diffusivity Along the Perivascular Space as Emerging Neuroimaging Biomarkers of Neurological Diseases.

The existence of lymphatic vessels or similar clearance systems in the central nervous system (CNS) that transport nutrients and remove cellular waste is a neuroscientific question of great significance. As the brain is the most metabolically active organ in the body, there is likely to be a potential correlation between its clearance system and the pathological state of the CNS. Until recently the successive discoveries of the glymphatic system and the meningeal lymphatics solved this puzzle. This article reviews the basic anatomy and physiology of the glymphatic system. Imaging techniques to visualize the function of the glymphatic system mainly including post-contrast imaging techniques, indirect lymphatic assessment by detecting increased perivascular space, and diffusion tensor image analysis along the perivascular space (DTI-ALPS) are discussed. The pathological link between glymphatic system dysfunction and neurological disorders is the key point, focusing on the enlarged perivascular space (EPVS) and the index of diffusivity along the perivascular space (ALPS index), which may represent the activity of the glymphatic system as possible clinical neuroimaging biomarkers of neurological disorders. The pathological link between glymphatic system dysfunction and neurological disorders is the key point, focusing on the enlarged perivascular space (EPVS) and the index for of diffusivity along the perivascular space (ALPS index), which may represent the activity of the glymphatic system as possible clinical neuroimaging biomarkers of neurological disorders.

Clinical application of magnetic resonance elastography in pediatric neurological disorders.

Magnetic resonance elastography is a relatively new, rapidly evolving quantitative magnetic resonance imaging technique which can be used for mapping the viscoelastic mechanical properties of soft tissues. MR elastography measurements are akin to manual palpation but with the advantages of both being quantitative and being useful for regions which are not available for palpation, such as the human brain. MR elastography is noninvasive, well tolerated, and complements standard radiological and histopathological studies by providing in vivo measurements that reflect tissue microstructural integrity. While brain MR elastography studies in adults are becoming frequent, published studies on the utility of MR elastography in children are sparse. In this review, we have summarized the major scientific principles and recent clinical applications of brain MR elastography in diagnostic neuroscience and discuss avenues for impact in assessing the pediatric brain.

Imaging Approaches to Investigate Pathophysiological Mechanisms of Brain Disease in Zebrafish.

Zebrafish has become an essential model organism in modern biomedical research. Owing to its distinctive features and high grade of genomic homology with humans, it is increasingly employed to model diverse neurological disorders, both through genetic and pharmacological intervention. The use of this vertebrate model has recently enhanced research efforts, both in the optical technology and in the bioengineering fields, aiming at developing novel tools for high spatiotemporal resolution imaging. Indeed, the ever-increasing use of imaging methods, often combined with fluorescent reporters or tags, enable a unique chance for translational neuroscience research at different levels, ranging from behavior (whole-organism) to functional aspects (whole-brain) and down to structural features (cellular and subcellular). In this work, we present a review of the imaging approaches employed to investigate pathophysiological mechanisms underlying functional, structural, and behavioral alterations of human neurological diseases modeled in zebrafish.

Distinct features in adult polyglucosan body disease: a case series.

Adult polyglucosan body disease (APBD) is caused by bi-allelic pathogenic variants in GBE1 and typically shows middle age onset urinary symptoms followed by progressive gait disturbances and possibly cognitive decline. Here we present a Belgian cohort of four patients from three families showing both classical and atypical signs of APBD. By clinical phenotyping, detailed neuroimaging of both central nervous system and skeletal muscle, genetic and biochemical testing, we confront our findings with the classical presentation of adult polyglucosan body disease and emphasize the importance of a multidisciplinary approach when diagnosing these patients.

Serum neurofilament light chain and initial severity of neurological disease predict the early neurological deterioration in Wilson's disease.

BACKGROUND: In Wilson's disease (WD), early neurological deterioration after treatment initiation is associated with poor outcomes; however, data on this phenomenon are limited. Our study analysed the frequency and risk factors of early neurological deterioration in WD. METHODS: Early neurological deterioration, within 6 months from diagnosis, was defined based on the Unified Wilson's Disease Rating Scale (UWDRS): any increase in part II or an increase of ≥ 4 in part III. In total, 61 newly diagnosed WD patients were included. UWDRS scores, brain magnetic resonance imaging (MRI) scores, copper metabolism parameters, treatment type and serum neuro-filament light chain (sNfL) concentrations at diagnosis were analysed as potential risk factors of early deterioration. RESULTS: Early neurological deterioration was observed in 16.3% of all WD patients; all cases of worsening occurred in the neurological phenotype (27.7%). Higher scores were seen in those who deteriorated compared with those who did not for UWDRS part II (4.3 ± 5.0 vs 2.0 ± 5.9; p < 0.05), UWDRS part III (21.5 ± 14.1 vs 9.3 ± 16.4; p < 0.01) and MRI-assessed chronic damage (3.2 ± 1.6 vs 1.4 ± 2.2; p = 0.006); all these variables indicated the initial severity of neurological disease. Pre-treatment sNfL concentrations were significantly higher in patients who deteriorated compared with those who did not (33.2 ± 23.5 vs 27.6 ± 62.7 pg/mL; p < 0.01). In univariate logistic regression amongst all patients, chronic damage MRI scores, UWDRS part III scores and sNfL concentrations predicated early deterioration. In the neurological WD, only sNFL were a significant predictor. In bivariate logistic regression amongst all patients, sNfL remained the only significant predictor of deterioration when corrected for MRI scores. CONCLUSION: sNfL concentrations are a promising biomarker of the risk of early neurological deterioration in WD.

Use of metal-based contrast agents for in vivo MR and CT imaging of phagocytic cells in neurological pathologies.

The activation of phagocytic cells is a hallmark of many neurological diseases. Imaging them in their 3-dimensional cerebral environment over time is crucial to better understand their role in disease pathogenesis and to monitor their potential therapeutic effects. Phagocytic cells have the ability to internalize metal-based contrast agents both in vitro and in vivo and can thus be tracked by magnetic resonance imaging (MRI) or computed tomography (CT). In this review article, we summarize the different labelling strategies, contrast agents, and in vivo imaging modalities that can be used to monitor cells with phagocytic activity in the central nervous system using MRI and CT, with a focus on clinical applications. Metal-based nanoparticle contrast agents such as gadolinium, gold and iron are ideal candidates for these applications as they have favourable magnetic and/or radiopaque properties and can be fine-tuned for optimal uptake by phagocytic cells. However, they also come with downsides due to their potential toxicity, especially in the brain where they might accumulate. We therefore conclude our review by discussing the pitfalls, safety and potential for clinical translation of these metal-based neuroimaging techniques. Early results in patients with neuropathologies such as multiple sclerosis, stroke, trauma, cerebral aneurysm and glioblastoma are promising. If the challenges represented by safety issues are overcome, phagocytic cells imaging will be a very valuable tool for studying and understanding the inflammatory response and evaluating treatments that aim at mitigating this response in patients with neurological diseases.

Pediatric Functional Neurological Disorder: Demographic and Clinical Factors Impacting Care.

This is a multicenter retrospective EMR-based chart review of 88 patients aged 3-21 years admitted for evaluation of functional neurologic disorder (FND). We sought to establish characteristics associated with FND, calculate incidence of abnormal neurodiagnostic findings, and determine features associated with variability in workup and treatment. FND patients were 65% female, 40% White, 33% Hispanic, and 88% primarily English speaking with median 13.9 years. We detected variability in management by age, ethnicity, psychiatric comorbidity, and hospital site. Our findings suggest limited utility to CTs in this setting (100% normal) and that workup can be safely informed by physical exam, which predicted abnormal MRI and LP results. We favor screening for adverse childhood experiences in FND patients. Hospitalization may be a rare opportunity for psychiatry contact.

A review on investigation of the basic contrast mechanism underlying multidimensional diffusion MRI in assessment of neurological disorders.

INTRODUCTION: Multidimensional diffusion MRI (MDD MRI) is a novel diffusion technique that uses advanced gradient waveforms for microstructural tissue characterization to provide information about average rate, anisotropy and orientation of the diffusion and to disentangle the signal fraction from specific cell types i.e., elongated cells, isotropic cells and free water. AIM: To review the diagnostic potential of MDD MRI in the clinical setting for microstructural tissue characterization in patients with neurological disorders to aid in patient care and treatment. METHOD: A scoping review on the clinical applications of MDD MRI was conducted from original articles published in PubMed and Scopus from 2015 to 2021 using the keywords "Multidimensional diffusion MRI" OR "diffusion tensor distribution" OR "Tensor-Valued Diffusion" OR "b-tensor encoding" OR "microscopic diffusion anisotropy" OR "microscopic anisotropy" OR "microscopic fractional anisotropy" OR "double diffusion encoding" OR "triple diffusion encoding" OR "double pulsed field gradients" OR "double wave vector" OR "correlation tensor imaging" AND "brain" OR "axons". RESULTS: Initially 145 articles were screened and after applying inclusion and exclusion criteria, nine articles were included in the final analysis. In most of these studies, microscopic diffusion anisotropy within the lesion showed deviation from the normal-appearing tissue. CONCLUSION: Multidimensional diffusion MRI can provide better quantification and visualization of tissue microstructure than conventional diffusion MRI and can be used in the clinical setting for diagnosis of neurological disorders.

Magnetic resonance spectroscopy as a promising modality for assessing ketogenic diet impact on the level of cerebral metabolites in the treatment of certain neurological disorders.

INTRODUCTION AND OBJECTIVE: The ketogenic diet (KD) is a high-fat, adequate-protein, low-carbohydrate diet that is getting more and more widespread in medicine. This dietary intervention causes changes in cerebral metabolism, which are considered potentially beneficial in patients with neurological disorders, but its impact should be controlled and assessed individually. The aim of this review is to provide an update of existing evidence concerning the utility of magnetic resonance spectroscopy (MRS) in monitoring shifts in the cerebral metabolism during ketogenic diet in patients with neurological disorders. REVIEW METHODS: The latest available literature was reviewed by May 13, 2021 using the PubMed, Web of Science and Google Scholar databases. There were 13 papers selected for analysis after reading the title, abstracts and whole text, meeting the assumed criteria. ABBREVIATED DESCRIPTION OF THE STATE OF KNOWLEDGE: MRS is a non-invasive imaging method providing information about the metabolism of brain tissues and playing an increasingly important role in monitoring the concentrations of cerebral metabolites in the course of such neurological disorders as primary brain tumour, epilepsy during KD. Recent trials prove that inverse correlation between serum ß-hydroxybutyrate levels and N-acetylaspartate in brain tissue confirm antiepileptogenic properties of KD. Furthermore, ketone concentrations including ß-hydroxybutyrate and acetone in both lesional and contralateral brain are referred to as correlating with average ketonuria in patients with primary brain tumou. SUMMARY: MRS is a feasible tool for detecting cerebral metabolic shifts linked to a ketogenic diet. However, further studies confirming MR spectroscopy utility in monitoring ketogenic diet treatment in patients with neurological disorders are needed.

Spatial normalization and quantification approaches of PET imaging for neurological disorders.

Quantification approaches of positron emission tomography (PET) imaging provide user-independent evaluation of pathophysiological processes in living brains, which have been strongly recommended in clinical diagnosis of neurological disorders. Most PET quantification approaches depend on spatial normalization of PET images to brain template; however, the spatial normalization and quantification approaches have not been comprehensively reviewed. In this review, we introduced and compared PET template-based and magnetic resonance imaging (MRI)-aided spatial normalization approaches. Tracer-specific and age-specific PET brain templates were surveyed between 1999 and 2021 for 18F-FDG, 11C-PIB, 18F-Florbetapir, 18F-THK5317, and etc., as well as adaptive PET template methods. Spatial normalization-based PET quantification approaches were reviewed, including region-of-interest (ROI)-based and voxel-wise quantitative methods. Spatial normalization-based ROI segmentation approaches were introduced, including manual delineation on template, atlas-based segmentation, and multi-atlas approach. Voxel-wise quantification approaches were reviewed, including voxel-wise statistics and principal component analysis. Certain concerns and representative examples of clinical applications were provided for both ROI-based and voxel-wise quantification approaches. At last, a recipe for PET spatial normalization and quantification approaches was concluded to improve diagnosis accuracy of neurological disorders in clinical practice.

Leptomeningeal enhancement in multiple sclerosis and other neurological diseases: A systematic review and Meta-Analysis.

BACKGROUND: The lack of systematic evidence on leptomeningeal enhancement (LME) on MRI in neurological diseases, including multiple sclerosis (MS), hampers its interpretation in clinical routine and research settings. PURPOSE: To perform a systematic review and meta-analysis of MRI LME in MS and other neurological diseases. MATERIALS AND METHODS: In a comprehensive literature search in Medline, Scopus, and Embase, out of 2292 publications, 459 records assessing LME in neurological diseases were eligible for qualitative synthesis. Of these, 135 were included in a random-effects model meta-analysis with subgroup analyses for MS. RESULTS: Of eligible publications, 161 investigated LME in neoplastic neurological (n = 2392), 91 in neuroinfectious (n = 1890), and 75 in primary neuroinflammatory diseases (n = 4038). The LME-proportions for these disease classes were 0.47 [95%-CI: 0.37-0.57], 0.59 [95%-CI: 0.47-0.69], and 0.26 [95%-CI: 0.20-0.35], respectively. In a subgroup analysis comprising 1605 MS cases, LME proportion was 0.30 [95%-CI 0.21-0.42] with lower proportions in relapsing-remitting (0.19 [95%-CI 0.13-0.27]) compared to progressive MS (0.39 [95%-CI 0.30-0.49], p = 0.002) and higher proportions in studies imaging at 7 T (0.79 [95%-CI 0.64-0.89]) compared to lower field strengths (0.21 [95%-CI 0.15-0.29], p < 0.001). LME in MS was associated with longer disease duration (mean difference 2.2 years [95%-CI 0.2-4.2], p = 0.03), higher Expanded Disability Status Scale (mean difference 0.6 points [95%-CI 0.2-1.0], p = 0.006), higher T1 (mean difference 1.6 ml [95%-CI 0.1-3.0], p = 0.04) and T2 lesion load (mean difference 5.9 ml [95%-CI 3.2-8.6], p < 0.001), and lower cortical volume (mean difference -21.3 ml [95%-CI -34.7--7.9], p = 0.002). CONCLUSIONS: Our study provides high-grade evidence for the substantial presence of LME in MS and a comprehensive panel of other neurological diseases. Our data could facilitate differential diagnosis of LME in clinical settings. Additionally, our meta-analysis corroborates that LME is associated with key clinical and imaging features of MS. PROSPERO No: CRD42021235026.

Neurological Soft Signs in Non-diabetic End Stage Renal Disease Patients: Evaluation and Prediction.

Patients on hemodialysis suffer from several serious complex neurological complications resulting in significant disability. Early detection of these complications during the asymptomatic phase may consent to early intervention to prevent or minimize the disability. To assess and predict neurological soft signs (NSS) in non-diabetic end-stage renal disease (ESRD) patients on hemodialysis (HD) who do not suffer any apparent neurological symptoms. An analytical, cross-sectional study was done in Hemodialysis units in the Suez Canal University Hospitals. 96 ESRD adult patients on hemodialysis are exposed to: Medical history was taken via personal interview, laboratory tests, and clinical assessment of NSS using Heidelberg scale, and brain CT was done for 50 high-risk patients (hypertensive or those on dialysis for more than 5 years) to detect the presence of any probable neuro-radiological brain abnormalities. 79.2% of our studied ESRD patients on HD had positive NSS with a mean value of total score 8.5 ± 5.9. Strong positive correlations were present between NSS and Hb levels, duration of hemodialysis, and hypertension. CT had revealed no abnormality. NSS represent a reliable, affordable tool for regular bedside assessment of ESRD patients with HD who do not suffer any neurological symptoms for early detection of asymptomatic neurological lesions, especially since the CT brain scan did not show such changes early. The duration of hemodialysis, Hb level, and hypertension were independent predictors for the occurrence of silent neurological lesions in ESRD patients.

PET imaging of reactive astrocytes in neurological disorders.

The reactive astrocytes manifest molecular, structural, and functional remodeling in injury, infection, or diseases of the CNS, which play a critical role in the pathological mechanism of neurological diseases. A growing need exists for dependable approach to better characterize the activation of astrocyte in vivo. As an advanced molecular imaging technology, positron emission tomography (PET) has the potential for visualizing biological activities at the cellular levels. In the review, we summarized the PET visualization strategies for reactive astrocytes and discussed the applications of astrocyte PET imaging in neurological diseases. Future studies are needed to pay more attention to the development of specific imaging agents for astrocytes and further improve our exploration of reactive astrocytes in various diseases.