Myelin Changes Research Articles

Effects of the Notch Signaling Pathway on Secondary Brain Changes Caused by Spinal Cord Injury in Mice.

Spinal cord injury (SCI) can cause secondary brain changes, leading to hypomyelination in the dorsolateral prefrontal cortex (dlPFC). Some studies have shown that notch signaling pathway activation can regulate oligodendrocyte maturation and myelination. The aim of this study was to investigate whether inhibition of the Notch signaling pathway can alleviate hypomyelination in the dlPFC caused by SCI. Moreover, we further investigated whether the changes in myelination in the dlPFC are associated with neuropathic pain following SCI. We established a mouse model of SCI and observed the changes in mechanical and thermal hyperalgesia. Western blotting and immunofluorescence were used to analyze the changes in myelination in the dlPFC. The results indicated the existence of a relationship between activation of the Notch signaling pathway and hypomyelination in the dlPFC and confirmed the existence of a relationship between hypomyelination in the dlPFC and decreases in mechanical and thermal hyperalgesia thresholds. In conclusion, these results suggested that the Notch signaling pathway is activated after SCI, leading to hypomyelination in the dlPFC, and that DAPT can inhibit the Notch signaling pathway and improve mechanical and thermal hyperalgesia thresholds. Our findings provide a new target for the treatment of neuropathic pain caused by SCI.

Perinatal exposure to fluoxetine and maternal adversity affect myelin-related gene expression and epigenetic regulation in the corticolimbic circuit of juvenile rats.

Many pregnant women experience symptoms of depression, and are often treated with selective serotonin reuptake inhibitor (SSRI) antidepressants, such as fluoxetine. In utero exposure to SSRIs and maternal depressive symptoms is associated with sex-specific effects on the brain and behavior. However, knowledge about the neurobiological mechanisms underlying these sex differences is limited. In addition, most animal research into developmental SSRI exposure neglects the influence of maternal adversity. Therefore, we used a rat model relevant to depression to investigate the molecular effects of perinatal fluoxetine exposure in male and female juvenile offspring. We performed RNA sequencing and targeted DNA methylation analyses on the prefrontal cortex and basolateral amygdala; key regions of the corticolimbic circuit. Perinatal fluoxetine enhanced myelin-related gene expression in the prefrontal cortex, while inhibiting it in the basolateral amygdala. SSRI exposure and maternal adversity interacted to affect expression of genes such as myelin-associated glycoprotein (Mag) and myelin basic protein (Mbp). We speculate that altered myelination reflects altered brain maturation. In addition, these effects are stronger in males than in females, resembling known behavioral outcomes. Finally, Mag and Mbp expression correlated with DNA methylation, highlighting epigenetic regulation as a potential mechanism for developmental fluoxetine-induced changes in myelination.

Excitable Axonal Domains Adapt to Sensory Deprivation in the Olfactory System

The axon initial segment (AIS), nodes of Ranvier, and the oligodendrocyte-derived myelin sheath have significant influence on the firing patterns of neurons and the faithful, coordinated transmission of action potentials (APs) to downstream brain regions. In the olfactory bulb (OB), olfactory discrimination tasks lead to adaptive changes in cell firing patterns, and the output signals must reliably travel large distances to other brain regions along highly myelinated tracts. Whether myelinated axons adapt to facilitate olfactory sensory processing is unknown. Here, we investigate the morphology and physiology of mitral cell (MC) axons in the olfactory system of adult male and female mice and show that unilateral sensory deprivation causes system-wide adaptations in axonal morphology and myelin thickness. MC spiking patterns and APs also adapted to sensory deprivation. Strikingly, myelination and MC physiology were altered on both the deprived and nondeprived sides, indicating system level adaptations to reduced sensory input. Our work demonstrates a previously unstudied mechanism of plasticity in the olfactory system.SIGNIFICANCE STATEMENTSuccessful transmission of information from the olfactory bulb (OB) to piriform cortex through the lateral olfactory tract (LOT) relies on synchronized arrival of action potentials (APs). The coincident arrival of APs is dependent on reliable generation of APs in the axon initial segment (AIS) and fast conduction mediated by axon myelination. Here, we studied changes in mitral cell (MC) firing and AIS structure as well as changes in myelination of the LOT on unilateral olfactory deprivation in the adult mouse. Strikingly, myelination and MC physiology were altered on both the deprived and nondeprived sides, indicating system level adaptations to reduced sensory input. Our work demonstrates a previously unstudied mechanism of plasticity in the olfactory system.

R2* relaxometry analysis for mapping of white matter alteration in Parkinson’s disease with mild cognitive impairment

BackgroundR2* relaxometry analysis combined with quantitative susceptibility mapping (QSM), which has high sensitivity to iron deposition, can distinguish microstructural changes of the white matter (WM) and iron deposition, thereby providing a sensitive and biologically specific measure of the WM owing to the changes in myelin and its surrounding environment. This study aimed to explore the microstructural WM alterations associated with cognitive impairment in patients with Parkinson’s disease (PD) using R2* relaxometry analysis combined with QSM. Materials and methodsWe enrolled 24 patients with PD and mild cognitive impairment (PD-MCI), 22 patients with PD and normal cognition (PD-CN), and 19 age- and sex-matched healthy controls (HC). All participants underwent Montreal Cognitive Assessment (MoCA) and brain magnetic resonance imaging, including structural three-dimensional T1-weighted images and multiple spoiled gradient echo sequence (mGRE). The R2* and susceptibility maps were estimated from the multiple magnitude images of mGRE. The susceptibility maps were used for verifying iron deposition in the WM. The voxel-based R2* of the entire WM and its correlation with cognitive performance were analyzed. ResultsIn the voxel-based group comparisons, the R2* in the PD-MCI group was lower in some WM regions, including the corpus callosum, than R2* in the PD-CN and HC groups. The mean susceptibility values in almost all brain regions were negative and close-to-zero values, indicating no detectable paramagnetic iron deposition in the WM of all subjects. There was a significant positive correlation between R2* and MoCA in some regions of the WM, mainly the corpus callosum and left hemisphere. ConclusionR2* relaxometry analysis for WM microstructural changes provided further biologic insights on demyelination and changes in the surrounding environment, supported by the QSM results demonstrating no iron existence. This analysis highlighted the potential for the early evaluation of cognitive decline in patients with PD.

Multiple Sclerosis and Aging: The Dynamics of Demyelination and Remyelination

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) leading to demyelination and neurodegeneration. Life expectancy and age of onset in MS patients have been rising over the last decades, and previous studies have shown that age affects disease progression. Therefore, age appears as one of the most important factors in accumulating disability in MS patients. Indeed, the degeneration of oligodendrocytes (OGDs) and OGD precursors (OPCs) increases with age, in association with increased inflammatory activity of astrocytes and microglia. Similarly, age-related neuronal changes such as mitochondrial alterations, an increase in oxidative stress, and disrupted paranodal junctions can impact myelin integrity. Conversely, once myelination is complete, the long-term integrity of axons depends on OGD supply of energy. These alterations determine pathological myelin changes consisting of myelin outfolding, splitting, and accumulation of multilamellar fragments. Overall, these data demonstrate that old mature OGDs lose their ability to produce and maintain healthy myelin over time, to induce de novo myelination, and to remodel pre-existing myelinated axons that contribute to neural plasticity in the CNS. Furthermore, as observed in other tissues, aging induces a general decline in regenerative processes and, not surprisingly, progressively hinders remyelination in MS. In this context, this review will provide an overview of the current knowledge of age-related changes occurring in cells of the oligodendroglial lineage and how they impact myelin synthesis, axonal degeneration, and remyelination efficiency.

Diffusely abnormal white matter converts to T2 lesion volume in the absence of MRI-detectable acute inflammation.

Diffusely abnormal white matter, characterised by biochemical changes of myelin in the absence of frank demyelination, has been associated with clinical progression in secondary progressive multiple sclerosis. However, little is known about changes of diffusely abnormal white matter over time and their relation to focal white matter lesions. The objectives of this work were: (i) to characterize the longitudinal evolution of focal white matter lesions, diffusely abnormal white matter and diffusely abnormal white matter that transforms into focal white matter lesions; and (ii) to determine whether gadolinium enhancement, known to be associated with the development of new focal white matter lesions, is also related to diffusely abnormal white matter voxels that transform into focal white matter lesions. Our data included 4220 MRI scans of 689 secondary progressive multiple sclerosis participants, followed for 156 weeks, and 2677 scans of 686 relapsing-remitting multiple sclerosis participants, followed for 96 weeks. Focal white matter lesions and diffusely abnormal white matter were segmented using a previously validated, automatic thresholding technique based on normalized T2 intensity values. Using longitudinally registered images, diffusely abnormal white matter voxels at each visit that transformed into focal white matter lesions on the last MRI scan as well as their overlap with gadolinium-enhancing lesion masks were identified. Our results showed that the average yearly rate of conversion of diffusely abnormal white matter to focal white matter lesions was 1.27 cm3 for secondary progressive multiple sclerosis and 0.80 cm3 for relapsing-remitting multiple sclerosis. Focal white matter lesions in secondary progressive multiple sclerosis participants significantly increased (t = 3.9; P = 0.0001) while diffusely abnormal white matter significantly decreased (t = -4.3 P < 0.0001) and the ratio of focal white matter lesions to diffusely abnormal white matter increased (t = 12.7; P < 0.00001). Relapsing-remitting multiple sclerosis participants also showed an increase in the focal white matter lesions to diffusely abnormal white matter ratio (t = 6.9; P < 0.00001) but without a significant change of the individual volumes. Gadolinium enhancement was associated with 7.3% and 18.7% of focal new T2 lesion formation in the infrequent scans of the relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis cohorts, respectively. In comparison, only 0.1% and 0.0% of diffusely abnormal white matter to focal white matter lesions voxels overlapped with gadolinium enhancement. We conclude that diffusely abnormal white matter transforms into focal white matter lesions over time in both relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis. Diffusely abnormal white matter appears to represent a form of pre-lesional pathology that contributes to T2 lesion volume increase over time, independent of new focal inflammation and gadolinium enhancement.

Widespread Cortical Demyelination in Geriatric Cases of Mild Traumatic Brain Injury and in Alzheimer’s Disease

Dynapenia, the age-related loss of skeletal muscle strength without the loss of muscle mass, significantly impacts the activities and quality of life of the aging population. Studies have shown that dynapenia occurs earlier in females than males in both human and rodent studies. Moreover, in females, estrogen deficiency has been shown to contribute to the loss of skeletal muscle strength as well as blunted recovery of strength after injury. The maintenance of skeletal muscle contractile function is vital to the overall health of women, especially as women live 1/3 of their life in an estrogen deficient state. Reversible protein phosphorylation is an indispensable post-translational modification, playing a key role in signal transduction pathways. Phosphorylation of skeletal muscle proteins have been shown to regulate sarcomeric function, excitation-contraction coupling, energy metabolism, and fiber-type composition. To define the physiological changes in the skeletal muscle phosphoproteome associated with estrogen deficiency, we used an ovariectomy model coupled with mass spectrometry. We identified, in total, 5,424 unique phosphorylation sites and 1,177 phosphoproteins in the tibialis anterior muscle. Ingenuity Pathway Analysis show decreased phosphorylation of contractile proteins and significant predicted inhibition of the upstream kinase, CDK6 (z-score -2.0) in ovariectomized compared to control muscles. Our results suggest that estrogen deficiency remodels the skeletal muscle phosphoproteome which may alter phosphorylation signaling that might contribute to the loss of strength in females.

Widespread Cortical Demyelination in Geriatric Cases of Mild Traumatic Brain Injury and in Alzheimer’s Disease

Extreme adverse events such as natural disasters can accelerate disease progression and promote chronic inflammation. These phenotypes also increase in prevalence with age, suggesting that experiencing adversity might accelerate aging of the immune system. Adversity can induce persistent gene regulatory changes which may mechanistically explain the immune similarities between aging and adversity. To test how immune system aging is accelerated following a natural disaster, we measured the impact of Hurricane Maria on peripheral blood immune cell gene expression in a population of free-ranging rhesus macaques (Macaca mulatta) from before (n=435) versus after (n=108) Hurricane Maria. Experiencing Hurricane Maria altered the expression of 260 genes (FDR<10%), which were primarily involved in the inflammatory response. There was significant overlap in these hurricane-affected and age-associated genes with 40% (n=104) being associated with both the hurricane and aging, more than double the expected amount (Fisher’s Exact Test OR=3.7, p=4.06 x 10–21). The effects of the hurricane and aging on gene expression were also significantly correlated (rho=0.23, p=1.33 x 10-84), suggesting that they alter similar molecular pathways in the immune system. Further, we found that animals that experienced the hurricane had a gene expression profile that was, on average, 1.6 years older than animals that did not experience the hurricane (the equivalent of 6–7 years in a human lifespan, p=0.003). Together, our results provide some of the first evidence that extreme natural disasters mechanistically accelerates aging in the immune system.

Myelin: A gatekeeper of activity-dependent circuit plasticity?

The brain is responsive to an ever-changing environment, enabling the organism to learn and change behavior accordingly. Efforts to understand the underpinnings of this plasticity have almost exclusively focused on the functional and underlying structural changes that neurons undergo at neurochemical synapses. What has received comparatively little attention is the involvement of activity-dependent myelination in such plasticity and the functional output of circuits controlling behavior. The traditionally held view of myelin as a passive insulator of axons is changing to one of lifelong changes in myelin, modulated by neuronal activity and experience. We review the nascent evidence of the functional role of myelin plasticity in strengthening circuit functions that underlie learning and behavior.

Myelination Deficits in the Auditory Brainstem of a Mouse Model of Fragile X Syndrome.

Auditory symptoms are one of the most frequent sensory issues described in people with Fragile X Syndrome (FXS), the most common genetic form of intellectual disability. However, the mechanisms that lead to these symptoms are under explored. In this study, we examined whether there are defects in myelination in the auditory brainstem circuitry. Specifically, we studied myelinated fibers that terminate in the Calyx of Held, which encode temporally precise sound arrival time, and are some of the most heavily myelinated axons in the brain. We measured anatomical myelination characteristics using coherent anti-stokes Raman spectroscopy (CARS) and electron microscopy (EM) in a FXS mouse model in the medial nucleus of the trapezoid body (MNTB) where the Calyx of Held synapses. We measured number of mature oligodendrocytes (OL) and oligodendrocyte precursor cells (OPCs) to determine if changes in myelination were due to changes in the number of myelinating or immature glial cells. The two microscopy techniques (EM and CARS) showed a decrease in fiber diameter in FXS mice. Additionally, EM results indicated reductions in myelin thickness and axon diameter, and an increase in g-ratio, a measure of structural and functional myelination. Lastly, we showed an increase in both OL and OPCs in MNTB sections of FXS mice suggesting that the myelination phenotype is not due to an overall decrease in number of myelinating OLs. This is the first study to show that a myelination defects in the auditory brainstem that may underly auditory phenotypes in FXS.

Periods of synchronized myelin changes shape brain function and plasticity.

Myelin, a lipid membrane that wraps axons, enabling fast neurotransmission and metabolic support to axons, is conventionally thought of as a static structure that is set early in development. However, recent evidence indicates that in the central nervous system (CNS), myelination is a protracted and plastic process, ongoing throughout adulthood. Importantly, myelin is emerging as a potential modulator of neuronal networks, and evidence from human studies has highlighted myelin as a major player in shaping human behavior and learning. Here we review how myelin changes throughout life and with learning. We discuss potential mechanisms of myelination at different life stages, explore whether myelin plasticity provides the regenerative potential of the CNS white matter, and question whether changes in myelin may underlie neurological disorders.

Longitudinal changes in brain parenchyma due to mild traumatic brain injury during the first year after injury.

Chronic gray matter (GM) atrophy is a known consequence of moderate and severe traumatic brain injuries but has not been consistently shown in mild traumatic brain injury (mTBI). The aim of this study was to investigate the longitudinal effect of uncomplicated mTBI on the brain's GM and white matter (WM) from 6 weeks to 12 months after injury. Voxel‐based‐morphometry (VBM) was computed with the T1‐weighted images of 48 uncomplicated mTBI patients and 37 orthopedic controls. Over the period from 6 weeks to 12 months, only patients who experienced uncomplicated mTBI, but not control participants, showed significant GM decrease predominantly in the right hemisphere along the GM‐CSF border in lateral and medial portions of the sensorimotor cortex extending into the rolandic operculum, middle frontal gyrus, insula, and temporal pole. Additionally, only mTBI patients, but not controls, experienced significant WM decrease predominantly in the right hemisphere in the superior fasciculus longitudinalis, arcuate fasciculus, and cortical‐pontine tracts as well as a significant WM increase in left arcuate fasciculus and left capsula extrema. We did not observe any significant change in the controls for the same time interval or any significant group differences in GM and WM probability at each of the two timepoints. This suggests that the changes along the brain tissue borders observed in the mTBI group represent a reorganization associated with subtle microscopical changes in intracortical myelin and not a direct degenerative process as a result of mTBI.

Post SRS Target Diffusion Metrics for Response Prognostication in Idiopathic Trigeminal Neuralgia

Diffusion tensor imaging (DTI) is used to measure the movement of water molecules in biological tissue, which permits a thorough characterization of white matter microstructure through quantitative diffusivity metrics. The most commonly used diffusivity metric, fractional anisotropy (FA), provides insight into the overall white matter microstructural properties, whereas radial diffusivity (RD), axial diffusivity (AD), and mean diffusivity (MD) suggest changes in myelination, axonal integrity & underlying neuro-inflammation and edema respectively. Study purpose is to find whether trigeminal nerve diffusivity metrics at a single, early time point after frameless SRS is predictive of long-term pain relief in patients with TN.Study cohort comprised of 44 pts with inclusion criteria were: 1) diagnosis of classic, type 1 TN 2) SRS treatment with no prior surgical procedures for TN; 3) 3 tesla MRI scans at 6 months posttreatment (range 5-7 months); and 4) at least 12 months of clinical follow-up. Patients with TN secondary to multiple sclerosis, cranial tumors, or vertebrobasilar dolichoectasia compressing the brainstem were excluded from the study. For each patient, diffusivity metrics (FA, MD, RD, and AD) were extracted from both the affected and unaffected trigeminal nerves at 6 months posttreatment 6 months diffusivity metrics were compared with long-term clinical outcome. Patients were identified as long-term responders if they achieved at least 75% reduction in preoperative pain for 12 months or longer following SRS. Average microstructural diffusivity differences (within group - pre and post treatment; across group - responder & non-responders) were analyzed using paired / Independent T test.Trigeminal nerve diffusivity at 6 months post-SRS was predictive of long-term clinical effectiveness, where long-term responders (n = 36) showed significantly lower fractional anisotropy at the radiosurgical target of their affected nerve compared to their contralateral, unaffected nerve and to nonresponders. Radial diffusivity and mean diffusivity, correlates of myelin alterations and inflammation, were also significantly higher in the affected nerve of long-term responders compared to their unaffected nerve. Nonresponders (n = 8) did not exhibit any characteristic diffusivity changes after SRS.DTI, FA specifically, appears to be a strong, objective measure to assess the effects of radiation on a nerve. Incorporating early DTI assessment can provide prognostic information that supplements clinical measures.

Clinical relevance of atrophy, myelin and iron brain microstructural alterations in multiple sclerosis: A multi-parameter MRI study

The concomitant presence of atrophy and microstructural abnormalities in multiple sclerosis (MS), as a results of the disease underlying physiopathology, is well documented. Nevertheless, the interplay between atrophy, iron e myelin changes remains elusive. Here we characterized their topography and their contribution to cognitive and motor disability.

18F-florbetapir PET as a marker of myelin integrity across the Alzheimer\u2019s disease spectrum

PurposeRecent evidence suggests that PET imaging with amyloid-β (Aβ) tracers can be used to assess myelin integrity in cerebral white matter (WM). Alzheimer’s disease (AD) is characterized by myelin changes that are believed to occur early in the disease course. Nevertheless, the extent to which demyelination, as measured with Aβ PET, contributes to AD progression remains unexplored.MethodsParticipants with concurrent 18F-florbetapir (FBP) PET, MRI, and cerebrospinal fluid (CSF) examinations were included (241 cognitively normal, 347 Aβ-positive cognitively impaired, and 207 Aβ-negative cognitively impaired subjects). A subset of these participants had also available diffusion tensor imaging (DTI) images (n = 195). We investigated cross-sectional associations of FBP retention in the white matter (WM) with MRI-based markers of WM degeneration, AD clinical progression, and fluid biomarkers. In longitudinal analyses, we used linear mixed models to assess whether FBP retention in normal-appearing WM (NAWM) predicted progression of WM hyperintensity (WMH) burden and clinical decline.ResultsIn AD-continuum individuals, FBP retention in NAWM was (1) higher compared with WMH regions, (2) associated with DTI-based measures of WM integrity, and (3) associated with longitudinal progression of WMH burden. FBP uptake in WM decreased across the AD continuum and with increasingly abnormal CSF biomarkers of AD. Furthermore, FBP retention in the WM was associated with large-calibre axon degeneration as reflected by abnormal plasma neurofilament light chain levels. Low FBP uptake in NAWM predicted clinical decline in preclinical and prodromal AD, independent of demographics, global cortical Aβ, and WMH burden. Most of these associations were also observed in Aβ-negative cognitively impaired individuals.ConclusionThese results support the hypothesis that FBP retention in the WM is myelin-related. Demyelination levels progressed across the AD continuum and were associated with clinical progression at early stages, suggesting that this pathologic process might be a relevant degenerative feature in the disease course.

Effects of electroacupuncture on myelin-related protein in corpus callosum of rats with focal cerebral ischemia

To observe the effect of electroacupuncture(EA)on the expression of myelin basic protein (MBP), axon growth inhibitor Nogo-A and Nogo receptor (NgR) in corpus callosum of rats with focal cerebral ischemia, so as to explore the mechanism of EA underlying improving ischemic white matter injury. Fourty male SD rats were randomly divided into normal, sham operation, model and EA groups, with 10 rats in each group. The focal cerebral ischemia rat model was established by occlusion of the middle cerebral artery (MCAO). EA was applied to "Baihui"(GV20) and "Zusanli"(ST36) on the left side for 30 min, once daily for 14 days. Neurological function score and the adhensive removal test were used to evaluate neurological deficit severity; Hematoxylin-esion staining was used to observe the pathological changes in myelin of corpus callosum and luxol fast blue（LFB） staining was used to observe the myelin of corpus callosum. Immunohistochemical staining and Western blot were used to detect the expressions of MBP、Nogo-A and NgR in the ischemic corpus callosum. After MCAO, the neurological function score was significantly increased (P<0.05), the time required for contact with tape and tape removal was longer (P<0.001), the intensity of LFB staining and the expression of MBP decreased, while the veside area and the expression of Nogo-A and its receptor NgR increased (P<0.01, P<0.05) in the model group relevant to the normal and sham operation groups. The fiber arrangement of the corpus callosum on the ischemic side was disordered and a large amount of myelin sheath was lost in the model group. Following the treatment, the neurological deficit score of EA group was gradually decreased and significantly decreased on the 3rd, 7th and 14th day (P<0.05), and the time to remove the adhesive tape was shortened at the 7th and 14th day (P<0.001). The shape of the corpus callosum in the EA group was close to normal, and the myelin structure was relatively complete. The intensity of LFB staining and the expression of MBP was increased (P<0.05, P<0.01) while the expression of Nogo-A and its receptor NgR were decreased in the EA group relevant to the model group (P<0.01). EA can play a protective role in myelin of the corpus callosum after cerebral ischemia, which may be related to down-regulating the expressions of Nogo-A and NgR.

Quantitative 7-Tesla Imaging of Cortical Myelin Changes in Early Multiple Sclerosis.

Cortical demyelination occurs early in multiple sclerosis (MS) and relates to disease outcome. The brain cortex has endogenous propensity for remyelination as proven from histopathology study. In this study, we aimed at characterizing cortical microstructural abnormalities related to myelin content by applying a novel quantitative MRI technique in early MS. A combined myelin estimation (CME) cortical map was obtained from quantitative 7-Tesla (7T) T and T1 acquisitions in 25 patients with early MS and 19 healthy volunteers. Cortical lesions in MS patients were classified based on their myelin content by comparison with CME values in healthy controls as demyelinated, partially demyelinated, or non-demyelinated. At follow-up, we registered changes in cortical lesions as increased, decreased, or stable CME. Vertex-wise analysis compared cortical CME in the normal-appearing cortex in 25 MS patients vs. 19 healthy controls at baseline and investigated longitudinal changes at 1 year in 10 MS patients. Measurements from the neurite orientation dispersion and density imaging (NODDI) diffusion model were obtained to account for cortical neurite/dendrite loss at baseline and follow-up. Finally, CME maps were correlated with clinical metrics. CME was overall low in cortical lesions (p = 0.03) and several normal-appearing cortical areas (p < 0.05) in the absence of NODDI abnormalities. Individual cortical lesion analysis revealed, however, heterogeneous CME patterns from extensive to partial or absent demyelination. At follow-up, CME overall decreased in cortical lesions and non-lesioned cortex, with few areas showing an increase (p < 0.05). Cortical CME maps correlated with processing speed in several areas across the cortex. In conclusion, CME allows detection of cortical microstructural changes related to coexisting demyelination and remyelination since the early phases of MS, and shows to be more sensitive than NODDI and relates to cognitive performance.

7T MRI Differentiates Remyelinated from Demyelinated Multiple Sclerosis Lesions.

ObjectiveTo noninvasively assess myelin status in chronic white matter lesions of multiple sclerosis (MS), we developed and evaluated a simple classification scheme based on T1 relaxation time maps derived from 7‐tesla postmortem and in vivo MRI.MethodsUsing the MP2RAGE MRI sequence, we classified 36 lesions from 4 postmortem MS brains as “long‐T1,” “short‐T1,” and “mixed‐T1” by visual comparison to neocortex. Within these groups, we compared T1 times to histologically derived measures of myelin and axons. We performed similar analysis of 235 chronic lesions with known date of onset in 25 MS cases in vivo and in a validation cohort of 222 lesions from 66 MS cases, investigating associations with clinical and radiological outcomes.ResultsPostmortem, lesions classified qualitatively as long‐T1, short‐T1, and mixed‐T1 corresponded to fully demyelinated, fully remyelinated, and mixed demyelinated/remyelinated lesions, respectively (p ≤ 0.001). Demyelination (rather than axon loss) dominantly contributed to initial T1 prolongation. We observed lesions with similar characteristics in vivo, allowing manual classification with substantial interrater and excellent intrarater reliability. Short‐T1 lesions were most common in the deep white matter, whereas long‐T1 and mixed‐T1 lesions were prevalent in the juxtacortical and periventricular white matter (p = 0.02) and were much more likely to have paramagnetic rims suggesting chronic inflammation (p < 0.001). Older age at the time of lesion formation portended less remyelination (p = 0.007).Interpretation7‐tesla T1 mapping with MP2RAGE, a clinically available MRI method, allows qualitative and quantitative classification of chronic MS lesions according to myelin content, rendering straightforward the tracking of lesional myelination changes over time. ANN NEUROL 2021;90:612–626

Connecting inside out: Development of the social brain in infants and toddlers with a focus on myelination as a marker of brain maturation.

Early childhood is a sensitive period for learning and social skill development. The maturation of cerebral regions underlying social processing lays the foundation for later social‐emotional competence. This study explored myelin changes in social brain regions and their association with changes in parent‐rated social‐emotional development in a cohort of 129 children (64 females, 0–36 months, 77 White). Results reveal a steep increase in myelination throughout the social brain in the first 3 years of life that is significantly associated with social‐emotional development scores. These findings add knowledge to the emerging picture of social brain development by describing neural underpinnings of human social behavior. They can contribute to identifying age‐/stage‐appropriate early life factors in this developmental domain.

Agricultural groundwater with high nitrates and dissolved salts given to pregnant mice alters brain development in the offspring

Groundwater is the main source of drinking water for a significant portion of the human population. In many agricultural areas, diffuse pollution such as high levels of total dissolved salts including nitrate, puts the quality of this resource at risk. However, the effect of exposure to these water contaminants on brain development is currently poorly understood. Here we characterised water from a borewell located in an intensely cultivated area (agricultural) or water from a borewell located in a nearby pristine forest. The agricultural borewell water was rich in nitrates with high total dissolved salts. We then studied the consequence of drinking the agricultural water on mouse brain development. For this, the agricultural borewell water or forest water was given to mice for 6 weeks before and during pregnancy and lactation. The brains of the offspring born to these dams were analysed at postnatal day (P)5 and P21 and compared using immunohistochemistry for changes in glial cells, neurons, myelin, and cell death across many brain regions. Brains from offspring born to dams who had been given agricultural water (versus forest control water) were significantly smaller, and at P21 had a significant degeneration of neurons and increased numbers of microglia in the motor cortex, had fewer white matter astrocytes and an increase in cell death, particularly in the dentate gyrus. This study shows that brain development is sensitive to water composition. It points to the importance of assessing neurodevelopmental delays when considering the effect of water contaminated with agricultural run offs on human health. Main findingPregnant and lactating mice were given borewell water from intensely cultivated land. Offspring brains reveal degeneration of neurons and a loss of astrocytes, increase in microglial cells and cell death, pointing to neurodevelopmental problems.