Increasing evidence indicates a potential role of white matter (WM) damage in the onset and progression of Alzheimer disease (AD). However, the biological processes underlying in vivo WM imaging biomarkers remain unclear. We sought to determine the molecular signatures associated with WM integrity in cognitively normal individuals with and without amyloid pathology. We selected older individuals without dementia (Clinical Dementia Rating <1) from the Alzheimer Centrum Amsterdam when they had diffusion tensor imaging (DTI) and CSF proteomic (untargeted tandem mass-mass spec) data available. Fractional anisotropy (FA) and mean diffusivity (MD) values were computed for the total WM and for 12 tracts of interest. We tested associations between protein levels (predictors) and both global and regional FA and MD values (outcomes) with linear models. Models further included an interaction between protein levels and amyloid status to evaluate specificity to disease. Gene-set and cell-type enrichment analyses were performed on proteins showing significant associations to characterize the underlying biological and cellular processes. A total of 96 participants were included in this study (mean age 67.82 ± 6.93 years; 45% male participants). A total of 234 protein levels (17.1%) were significantly associated with global DTI measures. Of these, 29.9% was unique for FA, and 29.9% for MD, while levels of the remaining proteins were associated with both measures (WM-generic proteins). WM-generic proteins were mostly enriched for pathways related to lipid metabolism and in endothelial cells, whereas proteins specific to FA were mostly related to blood coagulation and enriched in astrocytes and those specific to MD were mainly associated with processes related to actin filaments and enriched in oligodendrocytes. When looking at the interaction with amyloid status, both global FA and MD alterations in A+ participants were associated with biological processes of axonogenesis and synaptic plasticity. Regional analysis revealed distinct proteomic profiles associated with variations in regional FA and MD, with processes linked to synaptic plasticity specifically related to integrity of limbic fibers. Loss of WM integrity in the very early stages of AD seems to be related to alterations in biological processes associated with neuronal plasticity and oligodendrocyte integrity. Our findings provide new insights into the distinct biological mechanisms regulating WM integrity and its relationship with AD pathology.

Periventricular white matter hyperintensities (PWMHs) and regional brain glucose hypometabolism have each been linked to cognitive impairment, but their interplay independent of β-amyloid (Aβ) is unclear. This study examines whether PWMHs relate to region-specific cortical hypometabolism and metabolism mediates domain-specific cognition in Aβ-negative individuals. This retrospective cross-sectional study included 141 Aβ-negative patients with mild cognitive impairment (MCI) older than 50 years and 83 normal controls (NCs). All participants underwent 18F-fluorodeoxyglucose (FDG) PET, MRI and cognitive testing assessments at Severance Hospital, Yonsei University, between 2017 and 2022. PWMHs were defined as WMHs within 10 mm of the lateral ventricles; regional FDG standardized uptake value ratios were extracted from predefined cortical and limbic regions. Associations among PWMHs, metabolism, and cognition were tested using general linear models, and path analyses were conducted. The MCI and NC groups did not differ in age or sex. Greater PWMH burden correlated with lower FDG uptake, strongest in the posterior cingulate cortex (PCC) (β = -0.14; 95% CI -0.20 to -0.09; q < 0.001). PWMHs were related to lower executive (β = -0.41; 95% CI -0.74 to -0.08; q = 0.026), verbal memory (β = -0.73; 95% CI -1.16 to -0.30; q = 0.005), and visual memory (β = -0.62; 95% CI -1.01 to -0.23; q = 0.005) scores. Path analyses indicated indirect effects of PWMHs on executive function through hypometabolism in the frontal lobe (indirect β = -0.06; 95% CI -0.13 to -0.01; p = 0.016) and PCC (β = -0.12; 95% CI -0.20 to -0.04; p = 0.003), whereas direct effects were identified for verbal (β = -0.27; 95% CI -0.45 to -0.08; p = 0.006) and visual (β = -0.24; 95% CI -0.41 to -0.08; p = 0.005) memory. The effect of PWMHs on executive dysfunction was mediated by cortical hypometabolism, whereas memory dysfunction was directly driven by PWMHs. These findings suggest that incorporating 18F-FDG PET with MRI may enhance diagnostic and therapeutic stratification in clinical trials for vascular cognitive impairment.

The nature and interpretation of BOLD signals in white matter - A review.

Edaravone Dexborneol Promotes Oligodendrocyte Precursor Cell Proliferation and Differentiation to Repair White Matter and Improve Long-Term Outcomes after Ischemic Stroke.

White matter abnormalities in metabolic syndrome patients with and without mild cognitive impairment: A diffusion tensor imaging study.

Brain White Matter Microstructure in Middle and Older Aged Adults With Bipolar Disorder: A 2-Site Study.

Regional growth rates of white matter hyperintensities are associated with beta-amyloid burden.

Quasi-steady-state CEST for rapid and quantitative lesion detection in multiple sclerosis at 3T.

Suppression of microglial activation with anti-inflammatory drug bindarit enhances neural development in the shunt-treated neonatal hydrocephalus model rat.

Mapping the neural basis of selected cognitive functions: A combined functional, structural, and diffusion MRI study.

BackgroundTrials of deep brain stimulation (DBS) to the subcallosal cingulate gyrus (SCG) for treatment-resistant depression (TRD) have yielded mixed results. While open-label studies suggest effectiveness, randomized controlled trials (RCTs) have not consistently supported these findings. The study compared the efficacy of active versus sham SCG stimulation for TRD.MethodsParticipants (n = 35) in a major depressive episode and treatment resistance completed a 6-month double blind, crossover RCT, with an 18-month open-label phase. A Balaam design was applied with participants randomized to 1 of 4 stimulation groups over two 3-month phases. The primary outcome was a change in Hamilton Depression Rating Scale (HDRS) score at 6 months, with response defined as ≥50% reduction in HDRS-17 scores.ResultsWhile all groups showed improvement at 3 and 6 months, no significant differences were found among them. The OFF-OFF group had a numerically lower HDRS-17 score compared to the ON-ON group at the end of the RCT. No unexpected adverse events occurred. During the open-label phase, participants showed sustained reduction in HDRS-17 scores at 12, 18, and 24 months post-implantation, with successive observed-case response rates of 65.7%, 69%, and 73.1%, respectively. Improvements in life functioning were also noted.ConclusionsThis trial represents the largest single-centre, sham-controlled study of SCG DBS for TRD in the literature. Although the RCT showed no significant group differences, most participants achieved response during the open-label phase. Safety outcomes aligned with previous trials. Future RCTs should integrate insights from the past decade of DBS for TRD research to optimize outcomes. Key considerations include selecting DBS contact locations that ensure engagement of critical white matter tracts, employing novel and sufficiently long clinical trial designs to account for the non-specific effects of the DBS procedure, as well as incorporating biomarkers to guide DBS programming.

Diffusion-weighted magnetic resonance imaging (dMRI) in small animal models is often limited by long acquisition times, low signal-to-noise ratio (SNR) and magnetic susceptibility artefacts. We developed and optimised a 3D spin-echo multishot EPI (SE-msEPI) protocol combined with Gd-DOTA administration to enable efficient, high-quality exvivo diffusion imaging of the mouse brain. Systematic testing demonstrated that 12 EPI shots provided the optimal trade-off between artefact reduction, SNR and acquisition duration. Gd-DOTA incubation at 3 mM for 7 days allowed the TR to be reduced from 1500 to 400 ms without compromising diffusion metrics, yielding more than threefold SNR increase. This optimisation enabled whole-brain acquisitions at 100-μm isotropic resolution with 60 directions (b = 3000 s/mm2) in ~11 h, a fourfold acceleration compared to standard long-TR protocols. Fractional anisotropy values in Gd-DOTA-enhanced acquisitions closely matched those of the long-TR reference, while low-SNR short-TR baseline and postwashout acquisitions exhibited systematic FA underestimation. Residual error analysis and tractography performance metrics further demonstrated the improved image quality and anatomically plausible reconstruction of white matter pathways under Gd-DOTA-enhanced conditions. Beyond these technical gains, the optimised protocol provides a reproducible framework for high-throughput exvivo diffusion MRI, enabling connectomics and microstructural studies in mouse models with greater efficiency, increased reuse of tissue sample and reduced animal use.

Electroconvulsive therapy is associated with a decrease in anhedonia and axial diffusivity in the medial forebrain bundle in major depressive disorder.

Effect on disease activity of ofatumumab in the treatment of glial fibrillary acidic protein astrocytopathy and 18F-DPA714 PET/MRI imaging assessment.

Fronto-cerebellar features associate with cognitive dysfunction in childhood-onset systemic lupus erythematosus.

Gray matter atrophy and structural connectivity in Posterior Cortical Atrophy: A voxel-based meta-analysis.

Progress in neuroimaging research has provided insight into the neurobiological mechanism underlying depression, specifically motivational anhedonia, which compromises patients' ability to initiate goal-directed action. Breit etal. formerly, using the same cohort versus controls; correlations with reduced motivation were observed within superiority SLF and precuneus and authors emphasized that such results should pave the way to biomarkers in drug grounded development. This paper seeks to cross-fertilise neurobiological understandings of motivational anhedonia with novel therapeutic approaches, specifically showcasing how the confluence of rapid tele-psychotherapy with single-session music therapy (RTP-SSMT) represents a neurobiologically informed and scalable intervention for depressive disorders. Building on literature from diffusion tensor imaging (DTI) and resting-state fMRI, this review discusses the involvement of reduced local correlation in the precuneus-a key hub within DMN related to self-referential processing and rumination-coordinated with white matter alterations in the SLF connecting parietal and frontal cortices. It is suggested that RTP-SSMT may act to trigger dopaminergic reward pathways, re-normalize motivational circuits and augment behavioral activation tenets with a brief and technologically-driven approach. This paper also considers policy implications for incorporating creative-arts-based tele-therapies within stepped-care mental health services. The proposed model highlights how musically driven treatments have the potential to increase access, cultural appropriateness, and motivational engagement with mental health interventions. It urges clinicians and policymakers to consider evidence-informed, neurobiologically targeted interventions to enhance treatment adherence and provide psychotherapy more broadly in clinical and community settings. Integrating brain imaging results with new therapeutic concepts offers an opportunity for precision mental health care. Implementation of RTP-SSMT in mental health practice could revolutionize psychiatric treatment infrastructure for depression by integrating neuroscience, clinical innovation and policy to treat motivational anhedonia more effectively.

Previous research examining the contribution of white matter hyperintensities (WMHs) to cognitive decline has focused on overall lesion burden. A new approach, afforded by the Lesion Quantification Toolkit (LQT), measures localized connectivity disruption from WMHs to better estimate their impact on cognition. This methodology shifts the focus from lesion volume to the level of network disruption between brain regions. In this novel study, we applied the LQT approach to healthy aging and linked the degree of disconnection of gray matter by WMHs to both cognitive impairment and resilience via cognitive reserve. Using three pre-existing MRI datasets of older adults (total N = 259), we used the LQT to examine localized disruptions to brain connectivity due to WMHs. We then used partial least-squares path modeling to examine the relationships between this disruption, cognitive performance, age, and cognitive reserve. The results support a link between connectivity disruption and reduced cognitive performance. Results from all three individual datasets, one of which included a detailed measure of cognitive reserve, showed a link between cognitive reserve and higher cognitive performance, suggesting cognitive reserve allows for maintained cognitive function in spite of the negative impact of WMHs.

Cerebral small vessel disease (cSVD) is a common cause of stroke and dementia without available definitive treatments. Glucagon-like peptide-1 receptor (GLP-1R) agonists have revolutionized the management of diabetes and obesity and have shown benefits in reducing cardiovascular risk, but it remains unknown if they could lower the burden of cSVD manifestations. Here, we investigated associations between genetic variants that mimic the action of GLP-1R agonists and cSVD phenotypes. We applied a drug target Mendelian Randomization (MR) analysis using single-nucleotide polymorphisms (SNPs) within and near the GLP1R gene associated with reductions in HbA1c levels and body mass index (BMI). Our primary outcomes included the clinical end point of small vessel stroke (13,620 cases and 1,503,898 controls) and the imaging readout of white matter hyperintensity (WMH) volume (N = 48,454). The primary method used was inverse variance-weighted MR. Our GLP1R instruments consisted of 13 SNPs associated with HbA1c and 4 SNPs associated with BMI. After correcting for multiple comparisons, a genetically proxied reduction in HbA1c levels (per 6.75 mmol/mol) through perturbation in GLP1R was associated with lower odds of small vessel stroke (OR: 0.36, 95% CI 0.17-0.77, p = 0.008) and lower WMH volume on MRI (standardized beta: -0.52, 95% CI -0.84 to -0.19, p = 0.002). We observed similar, directionally consistent associations for genetically proxied GLP1R-driven BMI reduction (OR per 4.8 kg/m2 decrement for small vessel stroke: 0.18, 95% CI 0.03-0.95, p = 0.04; standardized beta for WMH volume: -0.75, 95% CI -1.50 to 0.00, p = 0.05). Our study found that genetically proxied GLP-1 receptor agonism is associated with lower burden of clinical and imaging cSVD outcomes. These findings provide a rationale for clinical trials evaluating GLP-1 receptor agonists as a potential strategy to prevent cSVD progression.

Mechanism of human umbilical cord mesenchymal stem cells in the treatment of germinal matrix hemorrhage-intraventricular hemorrhage.