The etiology and evolution of magnetic resonance imaging-visible perivascular spaces: Systematic review and meta-analysis

ObjectivesPerivascular spaces have been involved in neuroinflammatory and neurodegenerative diseases. Upon a certain size, these spaces can become visible on magnetic resonance imaging (MRI), referred to as enlarged perivascular spaces (EPVS) or MRI-visible perivascular spaces (MVPVS). However, the lack of systematic evidence on etiology and temporal dynamics of MVPVS hampers their diagnostic utility as MRI biomarker. Thus, the goal of this systematic review was to summarize potential etiologies and evolution of MVPVS.MethodsIn a comprehensive literature search, out of 1,488 unique publications, 140 records assessing etiopathogenesis and dynamics of MVPVS were eligible for a qualitative summary. 6 records were included in a meta-analysis to assess the association between MVPVS and brain atrophy.ResultsFour overarching and partly overlapping etiologies of MVPVS have been proposed: (1) Impairment of interstitial fluid circulation, (2) Spiral elongation of arteries, (3) Brain atrophy and/or perivascular myelin loss, and (4) Immune cell accumulation in the perivascular space. The meta-analysis in patients with neuroinflammatory diseases did not support an association between MVPVS and brain volume measures [R: −0.15 (95%-CI −0.40–0.11)]. Based on few and mostly small studies in tumefactive MVPVS and in vascular and neuroinflammatory diseases, temporal evolution of MVPVS is slow.ConclusionCollectively, this study provides high-grade evidence for MVPVS etiopathogenesis and temporal dynamics. Although several potential etiologies for MVPVS emergence have been proposed, they are only partially supported by data. Advanced MRI methods should be employed to further dissect etiopathogenesis and evolution of MVPVS. This can benefit their implementation as an imaging biomarker.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=346564, identifier CRD42022346564

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

Quantitative magnetic resonance mapping of the myelin bilayer reflects pathology in multiple sclerosis brain tissue

Multiple sclerosis (MS) is a neuroinflammatory disease characterized by loss of myelin (demyelination) and, to a certain extent, subsequent myelin repair (remyelination). To better understand the pathomechanisms underlying de- and remyelination and to monitor the efficacy of treatments aimed at regenerating myelin, techniques offering noninvasive visualizations of myelin are warranted. Magnetic resonance (MR) imaging has long been at the forefront of efforts to visualize myelin, but it has only recently become feasible to access the rapidly decaying resonance signals stemming from the myelin lipid-protein bilayer itself. Here, we show that direct MR mapping of the bilayer yields highly specific myelin maps in brain tissue from patients with MS. Furthermore, examination of the bilayer signal behavior is found to reveal pathological alterations in normal-appearing white and gray matter. These results indicate promise for in vivo implementations of the myelin bilayer mapping technique, with prospective applications in basic research, diagnostics, disease monitoring, and drug development

Cytotoxic lesions of the corpus callosum: a systematic review

OBJECTIVES Cytotoxic lesions of the corpus callosum (CLOCC) are a common magnetic resonance imaging (MRI) finding associated with various systemic diseases including COVID-19. Although an increasing number of such cases is reported in the literature, there is a lack of systematic evidence summarizing the etiology and neuroimaging findings of these lesions. Thus, the aim of this systematic review was to synthesize the applied nomenclature, neuroimaging and clinical features, and differential diagnoses as well as associated disease entities of CLOCC. MATERIALS AND METHODS A comprehensive literature search in three biomedical databases identified 441 references, out of which 324 were eligible for a narrative summary including a total of 1353 patients. RESULTS Our PRISMA-conform systematic review identifies a broad panel of disease entities which are associated with CLOCC, among them toxic/drug-treatment-associated, infectious (viral, bacterial), vascular, metabolic, traumatic, and neoplastic entities in both adult and pediatric individuals. On MRI, CLOCC show typical high T2 signal, low T1 signal, restricted diffusion, and lack of contrast enhancement. The majority of the lesions were reversible within the follow-up period (median follow-up 3 weeks). Interestingly, even though CLOCC were mostly associated with symptoms of the underlying disease, in exceptional cases, CLOCC were associated with callosal neurological symptoms. Of note, employed nomenclature for CLOCC was highly inconsistent. CONCLUSIONS Our study provides high-level evidence for clinical and imaging features of CLOCC as well as associated disease entities. CLINICAL RELEVANCE STATEMENT Our study provides high-level evidence on MRI features of CLOCC as well as a comprehensive list of disease entities potentially associated with CLOCC. Together, this will facilitate rigorous diagnostic workup of suspected CLOCC cases. KEY POINTS • Cytotoxic lesions of the corpus callosum (CLOCC) are a frequent MRI feature associated with various systemic diseases. • Cytotoxic lesions of the corpus callosum show a highly homogenous MRI presentation and temporal dynamics. • This comprehensive overview will benefit (neuro)radiologists during diagnostic workup

Outflow of cerebrospinal fluid is predominantly through lymphatic vessels and is reduced in aged mice.

Cerebrospinal fluid (CSF) has been commonly accepted to drain through arachnoid projections from the subarachnoid space to the dural venous sinuses. However, a lymphatic component to CSF outflow has long been known. Here, we utilize lymphatic-reporter mice and high-resolution stereomicroscopy to characterize the anatomical routes and dynamics of outflow of CSF. After infusion into a lateral ventricle, tracers spread into the paravascular spaces of the pia mater and cortex of the brain. Tracers also rapidly reach lymph nodes using perineural routes through foramina in the skull. Using noninvasive imaging techniques that can quantify the transport of tracers to the blood and lymph nodes, we find that lymphatic vessels are the major outflow pathway for both large and small molecular tracers in mice. A significant decline in CSF lymphatic outflow is found in aged compared to young mice, suggesting that the lymphatic system may represent a target for age-associated neurological conditions

Neuroimaging phenotypes of CSF1R-related leukoencephalopathy: Systematic review, meta-analysis, and imaging recommendations

Colony-stimulating factor 1 receptor (CSF1R)-related leukoencephalopathy is a rare but fatal microgliopathy. The diagnosis is often delayed due to multifaceted symptoms that can mimic several other neurological disorders. Imaging provides diagnostic clues that help identify cases. The objective of this study was to integrate the literature on neuroimaging phenotypes of CSF1R-related leukoencephalopathy. A systematic review and meta-analysis were performed for neuroimaging findings of CSF1R-related leukoencephalopathy via PubMed, Web of Science, and Embase on 25 August 2021. The search included cases with confirmed CSF1R mutations reported under the previous terms hereditary diffuse leukoencephalopathy with spheroids, pigmentary orthochromatic leukodystrophy, and adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. In 78 studies providing neuroimaging data, 195 cases were identified carrying CSF1R mutations in 14 exons and five introns. Women had a statistically significant earlier age of onset (p = 0.041, 40 vs 43 years). Mean delay between symptom onset and neuroimaging was 2.3 years. Main magnetic resonance imaging (MRI) findings were frontoparietal white matter lesions, callosal thinning, and foci of restricted diffusion. The hallmark computed tomography (CT) finding was white matter calcifications. Widespread cerebral hypometabolism and hypoperfusion were reported using positron emission tomography and single-photon emission computed tomography. In conclusion, CSF1R-related leukoencephalopathy is associated with progressive white matter lesions and brain atrophy that can resemble other neurodegenerative/-inflammatory disorders. However, long-lasting diffusion restriction and parenchymal calcifications are more specific findings that can aid the differential diagnosis. Native brain CT and brain MRI (with and without a contrast agent) are recommended with proposed protocols and pictorial examples are provided

Dilated Virchow-Robin spaces are a marker for arterial disease in multiple sclerosis

BACKGROUND Virchow-Robin spaces (VRS) have been associated with neurodegeneration and neuroinflammation. However, it remains uncertain to what degree non-dilated or dilated VRS reflect specific features of neuroinflammatory pathology. Thus, we aimed at investigating the clinical relevance of VRS as imaging biomarker in multiple sclerosis (MS) and to correlate VRS to their histopathologic signature. METHODS In a cohort study comprising 142 MS patients and 30 control subjects, we assessed the association of non-dilated and dilated VRS to clinical and magnetic resonance imaging (MRI) outcomes. Findings were corroborated in a validation cohort comprising 63 MS patients. Brain blocks from 6 MS patients and 3 non-MS controls were histopathologically processed to correlate VRS to their tissue substrate. FINDINGS In our actively treated clinical cohort, the count of dilated centrum semiovale VRS was associated with increased T1 and T2 lesion volumes. There was no systematic spatial colocalization of dilated VRS with MS lesions. At tissue level, VRS mostly corresponded to arteries and were not associated with MS pathological hallmarks. Interestingly, in our ex vivo cohort comprising mostly progressive MS patients, dilated VRS in MS were associated with signs of small vessel disease. INTERPRETATION Contrary to prior beliefs, these observations suggest that VRS in MS do not associate with an accumulation of immune cells. But instead, these findings indicate vascular pathology as a driver and/or consequence of neuroinflammatory pathology for this imaging feature. FUNDING NIH, Swedish Society for Medical Research, Swiss National Science Foundation and University of Zurich

Axonal mitochondria adjust in size depending on g-ratio of surrounding myelin during homeostasis and advanced remyelination

Demyelinating pathology is common in many neurological diseases such as multiple sclerosis, stroke, and Alzheimer's disease and results in axonal energy deficiency, dysfunctional axonal propagation, and neurodegeneration. During myelin repair and also during myelin homeostasis, mutual regulative processes between axons and myelin sheaths are known to be essential. However, proficient tools are lacking to characterize axon-myelin interdependence during (re)myelination. Thus, we herein investigated adaptions in myelin sheath g-ratio as a proxy for myelin thickness and axon metabolic status during homeostasis and myelin repair, by using axonal mitochondrial size as a proxy for axonal metabolic status. We found that axons with thinner myelin sheaths had larger axonal mitochondria; this was true for across different central nervous system tracts as well as across species, including humans. The link between myelin sheath thickness and mitochondrial size was temporarily absent during demyelination but reestablished during advanced remyelination, as shown in two commonly used animal models of toxic demyelination. By further exploring this association in mice with either genetically induced mitochondrial or myelin dysfunction, we show that axonal mitochondrial size adjusts in response to the thickness of the myelin sheath but not vice versa. This pinpoints the relevance of mitochondrial adaptation upon myelin repair and might open a new therapeutic window for remyelinating therapies