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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.

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.

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.

Autism spectrum disorder (ASD) is a high cost neurodevelopmental condition; and there are currently no effective pharmacological treatments for its core symptoms. This has led some families and researchers to trial alternative remedies – including the non-intoxicating Cannabis sativa-derived compound cannabidivarin (CBDV). However, how CBDV affects the human brain is unknown. Previous (pre)clinical evidence suggests that CBDV may modulate brain excitatory-inhibitory systems, which are implicated in ASD. Hence, our main aim was to test, for the first time, if CBDV shifts glutamate and/or GABA metabolites – markers of the brain’s primary excitatory and inhibitory system - in both the ‘typical’ and autistic brain. Our subsidiary aim was to determine whether, within ASD, brain responsivity to CBDV challenge is related to baseline biological phenotype. We tested this using a repeated-measures, double-blind, randomized-order, cross-over design. We used magnetic resonance spectroscopy (MRS) to compare glutamate (Glx = glutamate + glutamine) and GABA + (GABA + macromolecules) levels following placebo (baseline) and 600 mg CBDV in 34 healthy men with (n = 17) and without (n = 17) ASD. Data acquisition from regions previously reliably linked to ASD (dorsomedial prefrontal cortex, DMPFC; left basal ganglia, BG) commenced 2 h (peak plasma levels) after placebo/CBDV administration. Where CBDV significantly shifted metabolite levels, we examined the relationship of this change with baseline metabolite levels. Test sessions were at least 13 days apart to ensure CBDV wash-out. CBDV significantly increased Glx in the BG of both groups. However, this impact was not uniform across individuals. In the ASD group, and not in the typically developing controls, the ‘shift’ in Glx correlated negatively with baseline Glx concentration. In contrast, CBDV had no significant impact on Glx in the DMPFC, or on GABA+ in either voxel in either group. Our findings suggest that, as measured by MRS, CBDV modulates the glutamate-GABA system in the BG but not in frontal regions. Moreover, there is individual variation in response depending on baseline biochemistry. Future studies should examine the effect of CBDV on behaviour and if the response to an acute dose of CBDV could predict a potential clinical treatment response in ASD.

This study tested the efficacy of the phosphodiesterase type III inhibitor cilostazol in Alzheimer's disease patients with white matter lesions treated with donepezil in comparison with donepezil monotherapy using fluorodeoxyglucose (18F) positron-emission tomography (FDG PET). A 24-week, randomized, double-blind, placebo-controlled, parallel-group study was conducted. Thirty-six Alzheimer's disease patients with white matter lesions who received donepezil (n = 18 each in the cilostazol and placebo groups) were enrolled. Participants underwent pre and post FDG PET imaging scans and three rounds of clinical and neuropsychological tests. The cilostazol group did not show a significant decrease of regional glucose metabolism; however, regional glucose metabolism was significantly decreased in the parietal and frontal lobes of the placebo group. The repeated measures ANOVA measuring differences in uptake change revealed that regional glucose metabolism in the left inferior frontal gyrus was significantly more preserved in the cilostazol group than that in the placebo group (p < 0.005). Mean changes from baseline on the Mini-Mental State Exam, Alzheimer's Disease Assessment Scale-cognitive subscale, Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory, and the Clinical Dementia Rating Sum of Boxes did not differ between the two groups. In the cilostazol group, the increase of glucose metabolism correlated with the improvment of the Alzheimer's Disease Assessment Scale-cognitive score. We conclude that cilostazol treatment added to donepezil may delay the decline in regional cerebral metabolism in Alzheimer's disease with white matter lesions compared with donepezil monotherapy. In additon, our results verified the efficacy of cilostazol in improving or protecting cognitive function in Alzheimer's disease through increased glucose metabolism. However, the long-term effect of cilostazol on cognitive function and Alzheimer's disease modification must be tested in further studies with larger sample size and longer study period. Trial registration: http://clinicaltrials.gov: NCT01409564

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.

Abstract Background Selective serotonin reuptake inhibitors (SSRIs) are predominantly prescribed for people suffering from major depressive disorder. These antidepressants exert their effects by blocking the serotonin transporter (SERT), leading to increased levels of serotonin in the synaptic cleft and subsequently to an attenuation of depressive symptoms and elevation in mood. Although long-term studies investigating white matter (WM) alterations after exposure to antidepressant treatment exist, results on the acute effects on the brain’s WM microstructure are lacking. Methods In this interventional longitudinal study, 81 participants were included (33 patients and 48 healthy controls). All participants underwent diffusion weighted imaging on 2 separate days, receiving either citalopram or placebo using a randomized, double-blind, cross-over design. Fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity were calculated within the FMRIB software library and analyzed using tract-based spatial statistics. Results The repeated-measures ANOVA model revealed significant decreases after SSRI administration in mean diffusivity, axial diffusivity, and radial diffusivity regardless of the group (P < .05, family-wise error [FWE] corrected). Results were predominantly evident in frontal WM regions comprising the anterior corona radiata, corpus callosum, and external capsule and in distinct areas of the frontal blade. No increases in diffusivity were found, and no changes in fractional anisotropy were present. Conclusions Our investigation provides the first evidence, to our knowledge, that fast WM microstructure adaptations within 1 hour after i.v. SSRI administration precede elevations in mood due to SSRI treatment. These results add a new facet to the complex mode of action of antidepressant therapy. This study was registered at clinicaltrials.gov with the identifier NCT02711215.

Objective To assess the pathological mechanisms contributing to white matter (WM) lesion expansion or contraction and remyelination in multiple sclerosis (MS). Methods We assessed 1,613 lesions in 49 people with relapsing–remitting MS in the CCMR‐One bexarotene trial (EudraCT 2014‐003145‐99). We measured lesion orientation relative to WM tracts, surface‐in gradients and veins. Jacobian deformation was used to assess lesion expansion over 6 months, while magnetization transfer ratio (MTR) imaging was used to assess remyelination. Results At baseline, 33% of lesions were aligned with veins, 2% along WM tracts, 0% with surface‐in gradients, and 4% orthogonal to veins. No significant differences were observed in lesion shape, while lesions aligned with surface‐in gradients and with veins had lower volume compared to all remaining orientations. At follow‐up, 13% of lesions expanded and 7% contracted. The directions for both expansion and contraction were 18% and 8%, respectively, along WM tracts, 20% and 15% parallel to veins, 22% and 23% orthogonal to veins and 0% and 1% along surface‐in gradients. Bexarotene had no effect on lesion expansion or contraction, but MTR significantly increased in lesions aligned with surface‐in gradients and veins. Interpretation Lesion expansion and shrinkage are affected by venous and WM tract factors, but these do not influence bexarotene's capacity to promote remyelination. This, instead, appears to be affected by surface‐in factors. To limit lesion expansion and maximize tissue repair, multiple processes may need to be targeted. By applying the tensor model, we analysed lesion orientation and the directionality of lesion expansion/contraction in multiple sclerosis. Each lesion is summarized as an ellipsoid, and the tensor model is applied to calculate lesion anisotropy. From the top to the bottom white matter atlas, surface‐in gradient segmentation and venous atlas used in the present study are represented together with examples of lesions aligned with each orientation assessed.

Background In premature children, erythropoiesis-stimulating agents (ESAs) may improve developmental outcome. It is not clear which of the several potential mechanisms are responsible for this improvement. High-resolution MRI and diffusion tensor imaging characterize brain structure and white matter organization, offering possible insight into the long-term effect of ESAs on brain development. Methods MRI scans were performed at 3.5–4 years of age on former preterm infants treated with ESAs or placebo, and on healthy term controls. Mean cortical thickness, surface area, and fractional anisotropy (FA) were compared across study groups, and were correlated with general IQ measures. Results Univariate analysis found no significant effect of ESAs on cortical thickness ( P =0.366), surface area ( P =0.940), or FA ( P =0.150); however, there was a greater increase in FA among ESA-treated girls. Group analysis found significant correlations between FA and Full-Scale IQ ( P =0.044) and Verbal IQ ( P =0.036), although there was no significant relationship between Full-Scale IQ and FA among just the preterm children. Conclusion ESA treatment may have a preferential effect on white matter development in girls, although factors other than just whole-brain FA are involved in mediating cognitive outcome.

Background White matter lesions(WML) is an important cause of mild cognitive impairment(MCI). Ginkgo biloba extracts (GBTs) are widely used to treat cognitive dysfunctions. But the treatment of MCI is still limited. Shenqingtongqiao Decoction(SQTQD), as a clinical empirical formula, has received good feedback in treating MCI of WML. However, there was a lack of solid clinical research on SQTQD in treating MCI. The purpose of this study is to evaluate the efficacy of SQTQD in the MCI patients of WML. Methods This is a randomized, double-blind, double-dummy, parallel-controlled trial. 80 participants will be assigned to receive SQTQD granules plus GBTs mimetics or SQTQD mimetic granules plus GBTs in a 1:1 ratio. The trial will last 24 weeks, including a 12-week intervention and 12-week follow-up. The primary outcome is MoCA and AVLT. The secondary outcome is a neuropsychological battery (including MMSE, SCWT, TMT, DST, SDMT, BNT, VFT, and CDT), quality of life(BI, ADL, and FAQ scores), emotion assessment(PHQ-9, GAD-7 score) , Fazekas and ARWMCs scale, and fMRI. Researchers will record any adverse events throughout the trial. Discussion This study will provide evidence to evaluate the efficacy and safety of SQTQD for MCI of WML compared with GBTs. Trial registration The trial is registered at Chinese Clinical Trial Registry: Chinese Clinical Trial Registry (Number: ChiCTR2300068552).