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Growing evidence points to the pivotal role of vitamin D in the pathophysiology and treatment of major depressive disorder (MDD). However, there is a paucity of longitudinal research investigating the effects of vitamin D supplementation on the brain of MDD patients. We conducted a double-blind randomized controlled trial in 46 MDD patients, who were randomly allocated into either VD (antidepressant medication + vitamin D supplementation) or NVD (antidepressant medication + placebos) groups. Data from diffusion tensor imaging, resting-state functional MRI, serum vitamin D concentration, and clinical symptoms were obtained at baseline and after an average of 7 months of intervention. Both VD and NVD groups showed significant improvement in depression and anxiety symptoms but with no significant differences between the two groups. However, a greater increase in serum vitamin D concentration was found to be associated with greater improvement in depression and anxiety symptoms in VD group. More importantly, neuroimaging data demonstrated disrupted white matter integrity of right inferior fronto-occipital fasciculus along with decreased functional connectivity between right frontoparietal and medial visual networks after intervention in NVD group, but no changes in VD group. These findings suggest that vitamin D supplementation as adjunctive therapy to antidepressants may not only contribute to improvement in clinical symptoms but also help preserve brain structural and functional connectivity in MDD patients.

We present a new software package with a library of standardised tractography protocols devised for the robust automated extraction of white matter tracts both in the human and the macaque brain. Using in vivo data from the Human Connectome Project (HCP) and the UK Biobank and ex vivo data for the macaque brain datasets, we obtain white matter atlases, as well as atlases for tract endpoints on the white-grey matter boundary, for both species. We illustrate that our protocols are robust against data quality, generalisable across two species and reflect the known anatomy. We further demonstrate that they capture inter-subject variability by preserving tract lateralisation in humans and tract similarities stemming from twinship in the HCP cohort. Our results demonstrate that the presented toolbox will be useful for generating imaging-derived features in large cohorts, and in facilitating comparative neuroanatomy studies. The software, tractography protocols, and atlases are publicly released through FSL, allowing users to define their own tractography protocols in a standardised manner, further contributing to open science. •A new software package for standardised and automated cross-species tractography.•Homologous white matter bundles in the human and macaque brain.•Human white matter tract atlases generated from large datasets (1000 subjects).•Tractography protocols are standardised, but preserve individual variability.•Generalisability across datasets shown using the HCP and the UK Biobank data.

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials. White matter hyperintensities (WMH) are a common brain-imaging feature of cerebral small vessel disease. Here, the authors carry out a GWAS and followup analyses for WMH-volume, implicating several variants with potential for risk stratification and drug targeting.

Throughout infancy, childhood, and adolescence, our brains undergo remarkable changes. Processes including myelination and synaptogenesis occur rapidly across the first 2–3 years of life, and ongoing brain remodeling continues into young adulthood. Studies have sought to characterize the patterns of structural brain development, and early studies predominately relied upon gross anatomical measures of brain structure, morphology, and organization. MRI offers the ability to characterize and quantify a range of microstructural aspects of brain tissue that may be more closely related to fundamental neurodevelopmental processes. Techniques such as diffusion, magnetization transfer, relaxometry, and myelin water imaging provide insight into changing cyto- and myeloarchitecture, neuronal density, and structural connectivity. In this review, we focus on the growing body of literature exploiting these MRI techniques to better understand the microstructural changes that occur in brain white matter during maturation. Our review focuses on studies of normative brain development from birth to early adulthood (∼25 years), and places particular emphasis on longitudinal studies and newer techniques that are being used to study microstructural white matter development. All imaging methods demonstrate consistent, rapid microstructural white matter development over the first 3 years of life, suggesting increased myelination and axonal packing. Diffusion studies clearly demonstrate continued white matter maturation during later childhood and adolescence, though the lack of consistent findings in other modalities suggests changes may be mainly due to axonal packing. An emerging literature details differential microstructural development in boys and girls, and connects developmental trajectories to cognitive abilities, behaviour, and/or environmental factors, though the nature of these relationships remains unclear. Future research will need to focus on newer imaging techniques and longitudinal studies to provide more detailed information about microstructural white matter development, particularly in the childhood years. [Display omitted]

Valiltramiprosate/ALZ-801, an oral inhibitor of amyloid oligomer formation, was evaluated in a Phase 3 trial in APOE4/4 subjects with Early AD. While the study did not meet its primary clinical endpoint, volumetric MRI (vMRI) showed significant brain atrophy slowing. The pre-specified MCI subgroup showed positive effects on both clinical and vMRI outcomes. Amyloid oligomers are hypothesized to cause synaptic dysfunction and axonal damage, leading to microstructural changes and volume loss. The effects of valiltramiprosate on microstructural tissue changes in grey/white matter (GM, WM) were investigated using mean water diffusivity (MD) on diffusion MRI (dMRI-MD). This study enrolled 325 APOE4/4 homozygotes (162 placebo, 163 valiltramirposate) stratified by MCI/Mild AD. The ADAS-Cog13/CDR-SB were primary/key secondary outcomes; hippocampal volume and cortical thickness (HV, CT) were main/secondary vMRI outcomes, respectively. dMRI from 1.5/3 Tesla scanners were centrally analyzed by Clario Inc. (lower MD indicates tissue preservation). MMRM was primary analysis; Pearson's correlations were conducted. The clinical/vMRI datasets included 320/290 subjects respectively; dMRI included 206 subjects (84 MCI, 122 Mild AD). In the overall population, valiltramiprosate effects on MD compared to placebo showed positive trends (p <0.1) on cingulate/occipital cortex and caudate/striatum, and significant WM effects (corpus callosum genu [GCC] p <0.001; fornix p =0.007). Mild AD showed positive trends on occipital cortex and significant WM effects (GCC p =0.005; fornix p =0.019). MCI showed significant effects in cingulate (p =0.031) and WM (GCC/whole CC: p =0.003/0.013) and fornix (p =0.032). In MCI active arm, dMRI effects correlated significantly with clinical and volumetric effects. Frontal cortex MD correlated significantly with ADAS-Cog13/CDR-SB (p < 0.05) and HV and CT (both p =0.002). WM-GCC diffusivity correlations to HV (p =0.03) and CT were significant (p =0.006). Consistent with valiltramiprosate's effects on brain volumes, its effects on microstructural integrity were most prominent in the MCI subgroup that showed lower diffusivity in the cingulate cortex and major hippocampal outflow tracts. This microstructural preservation correlated significantly with preservation of HV/CT and with clinical benefits. These findings support valiltramiprosate's proposed mechanism: inhibiting oligomer formation may directly protect synapses/axons from damage, thus slowing neurodegeneration at a microstructural level and contributing to macrostructural preservation of brain volumes and clinical benefit.

Preclinical imaging studies offer a unique access to the rat brain, allowing investigations that go beyond what is possible in human studies. Unfortunately, these techniques still suffer from a lack of dedicated and standardized neuroimaging tools, namely brain templates and descriptive atlases. Here, we present two rat brain MRI templates and their associated gray matter, white matter and cerebrospinal fluid probability maps, generated from ex vivo T 2 * -weighted images (90 µm isotropic resolution) and in vivo T 2 -weighted images (150 µm isotropic resolution). In association with these templates, we also provide both anatomical and functional 3D brain atlases, respectively derived from the merging of the Waxholm and Tohoku atlases, and analysis of resting-state functional MRI data. Finally, we propose a complete set of preclinical MRI reference resources, compatible with common neuroimaging software, for the investigation of rat brain structures and functions. Magnetic resonance imaging (MRI) is widely used to study the rat brain. Here, the authors provide standardized MRI brain templates and descriptive atlases for the rat, incorporating both structural and functional MRI data, along with associated resources.

Adjuvant chemotherapy (CT) for breast cancer (BC) is associated with very late side-effects on brain function and structure. However, little is known about neurotoxicity of specific treatment regimens. To compare neurotoxicity profiles after different treatment strategies, we used neurocognitive testing and multimodality MRI in BC survivors randomized to high-dose (HI), conventional-dose (CON-) CT or radiotherapy (RT) only and a healthy control (HC) group. BC survivors who received CON-CT ( n  = 20) and HC ( n  = 20) were assessed using a neurocognitive test battery and multimodality MRI including 3D-T1, Diffusion Tensor Imaging (DTI) and 1H-MR spectroscopy (1H-MRS) to measure various aspects of cerebral white (WM) and gray matter (GM). Data were compared to previously assessed groups of BC survivors who received HI-CT ( n  = 17) and RT-only ( n  = 15). Testing took place on average 11.5 years post-CT. 3D-T1 showed focal GM volume reductions both for HI-CT and CON-CT compared to RT-only ( p  < .004). DTI-derived mean diffusivity and 1H-MRS derived N-acetyl aspartate showed WM injury specific to HI-CT but not CON-CT ( p  < .05). Residual effects were revealed in the RT-only group compared to HC on MRI and neurocognitive measurements ( p  < .05). Ten years after adjuvant CT for BC lower cerebral GM volume was found in HI as well as CON-CT BC survivors whereas injury to WM is restricted to HI-CT. This might indicate that WM brain changes after BC treatment may show more pronounced (partial) recovery than GM. Furthermore, our results suggest residual neurotoxicity in the RT-only group, which warrants further investigation.

The mapping of human brain connections is still an on going task. Unlike deep white matter (DWM), which has been extensively studied and well documented, superficial white matter (SWM) has been often left aside. Improving our understanding of the SWM is an important goal for a better understanding of the brain network and its relation to several pathologies. The shape and localization of these short bundles present a high variability across subjects. Furthermore, the small diameter of most superficial bundles and partial volume effects induced by their proximity to the cortex leads to complex tratography issues. Therefore, the mapping of SWM bundles and the use of the resulting atlases for clinical studies requiere dedicated methodologies that are reviewed in this paper. •Superficial White Matter (SWM) is important to better understand the brain network and its relation to several pathologies.•We describe the main approaches used for the study of SWM based on diffusion MRI and some application examples.•A descriptive comparison between different diffusion models and tractography methods for the study of SWM is also included, as well as an analysis of short association bundle reproducibility, based on the state-of-the-art bundle atlases.

Microglia, the resident myeloid cells in the central nervous system (CNS) play critical roles in shaping the brain during development, responding to invading pathogens, and clearing tissue debris or aberrant protein aggregations during ageing and neurodegeneration. The original concept that like macrophages, microglia are either damaging (pro-inflammatory) or regenerative (anti-inflammatory) has been updated to a kaleidoscope view of microglia phenotypes reflecting their wide-ranging roles in maintaining homeostasis in the CNS and, their contribution to CNS diseases, as well as aiding repair. The use of new technologies including single cell/nucleus RNA sequencing has led to the identification of many novel microglia states, allowing for a better understanding of their complexity and distinguishing regional variations in the CNS. This has also revealed differences between species and diseases, and between microglia and other myeloid cells in the CNS. However, most of the data on microglia heterogeneity have been generated on cells isolated from the cortex or whole brain, whereas white matter changes and differences between white and grey matter have been relatively understudied. Considering the importance of microglia in regulating white matter health, we provide a brief update on the current knowledge of microglia heterogeneity in the white matter, how microglia are important for the development of the CNS, and how microglial ageing affects CNS white matter homeostasis. We discuss how microglia are intricately linked to the classical white matter diseases such as multiple sclerosis and genetic white matter diseases, and their putative roles in neurodegenerative diseases in which white matter is also affected. Understanding the wide variety of microglial functions in the white matter may provide the basis for microglial targeted therapies for CNS diseases.

Histamine H 3 receptor blockade may enhance lesion remyelination in multiple sclerosis (MS). The efficacy (using a magnetic resonance imaging marker of myelination, magnetisation transfer ratio [MTR]), safety and pharmacokinetics of GSK239512, a potent and brain penetrant H 3 receptor antagonist/inverse agonist on lesion remyelination in relapsing-remitting MS (RRMS) were assessed. This was a phase II, randomised, parallel-group, placebo-controlled, double-blind (sponsor-unblinded), international, multicentre study (NCT01772199). Patients aged 18–50 with RRMS, receiving intramuscular interferon-β1a or glatiramer acetate, were randomised 1:1 to once-daily oral GSK239512 or placebo, up-titrated over 4–5 weeks to a maximum tolerable dose up to 80 µg and maintained until Week 48. The co-primary endpoints were mean changes in post-lesion MTR in gadolinium-enhanced (GdE) or Delta-MTR defined lesions from pre-lesion values. Adverse events (AE) and withdrawals were monitored. Of the 131 patients randomised, 114 patients completed the study (GSK239512, n  = 51; placebo, n  = 63) and 27 (GSK239512) and 28 (placebo) patients contributed lesions to the primary analysis. GSK239512 was associated with positive effect sizes of 0.344 [90% confidence interval (CI) 0.018, 0.671] and 0.243 (90% CI −0.112, 0.598) for adjusted mean changes in the normalised MTR for GdE and Delta-MTR lesions, respectively. The overall incidence of AEs was similar between GSK239512 and placebo during the treatment phase although some AEs including insomnia were more common with GSK239512, particularly during the titration period. A small but positive effect of GSK239512 on remyelination was observed. MTR assessment represents a promising method for detecting lesion remyelination in RRMS.