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.

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

Many patients with neurodegenerative and psychiatric diseases, such as Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD), suffer from apathy, which manifests as a lack of emotion, interest, and motivation. Therefore, research on the relationship between apathy and brain structure in patients with the disease is accumulating. However, the relationship between the tendency for apathy and brain structure in healthy people has hardly been clarified. Since changes in the brain's microstructure can occur even in individuals before they develop a specific disease, it is meaningful from the perspective of preventive medicine to clarify the latent apathy and changes in brain structure in healthy people. In addition, it is unclear and worth clarifying how apathy relates to the relationship between depression, which shares some symptoms with apathy, and the brain. Therefore, in this study, using diffusion tensor imaging data collected from 173 participants (69 men and 104 women) aged 23-69 years, along with responses to two psychological questionnaires (the Apathy Scale and the Center for Epidemiologic Studies Depression Scale), we analyzed the relationship between apathy and fractional anisotropy (FA) of four fibers, the uncinate fasciculus (UF), corpus callosum (CC), superior longitudinal fasciculus (SLF), and cingulum. As a result, there was a significant negative correlation between UF FA and apathy (p = 0.003), like previous studies in patients with AD and bvFTD. This relationship remained almost unchanged in partial correlation analysis controlling for sex, age, whole brain gray matter volume (GMV), depression, etc. (p = 0.001). Furthermore, the results of path analysis showed that apathy fully mediated the relationship between UF FA and depression (p = 0.001). This is the first study to show that apathy tendency in people who perceive themselves as healthy is associated with UF FA and mediates the relationship between UF FA and depression.

Quantitative assessment of early intervertebral disc degeneration with MR diffusion kurtosis imaging: A radiologic correlation with Pfirrmann grade.

Right-hemisphere glymphatic dysfunction is associated depressive symptoms in subacute stroke: A diffusion tensor imaging-along the perivascular space index study.

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

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

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

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.

The link between repetitive head impact (RHI) exposure, later-life cognitive decline, and neurobehavioral dysregulation (NBD) is not well understood. Recent work has implicated inflammation and limbic dysfunction as relevant RHI correlates. Our goal was to integrate plasma and CSF inflammatory biomarkers, structural brain imaging, and clinical measures in former elite American football players to better understand reasons for RHI-related cognitive and neurobehavioral changes. Participants were from the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy Research Project, which recruited male former college/professional football players with RHI and asymptomatic unexposed (UE) controls with no history of contact sports, military combat, or traumatic brain injury/concussion. Our study focused on plasma/CSF inflammatory biomarkers (interleukin [IL]-6, tumor necrosis factor [TNF]-α, glial fibrillary acidic protein), limbic white matter (WM) microstructure (diffusion tensor imaging: fractional anisotropy [FA], mean diffusivity [MD]), and clinical measures (memory, executive function, NBD). Hierarchical linear regressions assessed change in variance explained (ΔR2) among inflammation, WM, and clinical outcomes in former football players. Post hoc analyses tested whether associations differed by group (football vs UE; group interactions) or were stronger in football players considered at highest risk of CTE. Our sample included 223 men (n = 170 football players: age 57.2 ± 8.1 years, 33% non-Hispanic/Black; n = 53 UE participants: age 59.4 ± 8.6 years, 34% non-Hispanic/Black). In football players, higher inflammation was associated with lower limbic FA (plasma IL-6: ΔR2 = 0.03 [0.001-0.09], p = 0.03; CSF IL-6: ΔR2 = 0.03 [-0.01 to 0.11], p = 0.03; plasma TNF-α: ΔR2 = 0.05 [0.01-0.11], p = 0.003) and higher limbic MD (CSF IL-6: ΔR2 = 0.06 [0.007-0.15], p = 0.01). Inflammation was more strongly related to limbic WM microstructure in football players than in UE participants. Worse WM microstructure was associated with worse memory in football players (FA: ΔR2 = 0.05 [0.003-0.14], p = 0.007; MD: ΔR2 = 0.07, p = 0.003 [0.008-0.16]). Most of the observed associations were stronger in the CTE probable subgroup. There were no direct associations between plasma or CSF markers of inflammation and cognition. In former elite football players, elevated plasma and CSF inflammatory markers were associated with poorer limbic WM microstructure, which in turn related to worse cognition. Given the limbic system's role in cognition and behavior, inflammation may be a modifiable target for RHI-related neurodegeneration. Limitations include the cross-sectional design and limited generalizability to other contact sports, lower levels of play, female athletes, or other RHI sources.

Objective: To identify potential clinical subgroups among parents who lost their only child and compare inter-subgroup differences in brain structure and function. Methods: Parents who lost their only child and participated in a psychological assistance program organized by the local civil affairs department in Southern Jiangsu, China, between April 2021 and June 2022 were retrospectively recruited. They were randomly divided into a discovery set and a validation set in a 1∶1 ratio using a random number table. Assessments included the Clinician Administered Post-Traumatic Stress Disorder Scale (CAPS), the 24-item Hamilton Depression Rating Scale (HAMD-24), and the Hamilton Anxiety Rating Scale (HAMA). Seven symptom dimension factors were extracted: re-experiencing, avoidance, hyperarousal, depressive mood, somatic/anxiety, psychic anxiety, and somatic anxiety. Hierarchical clustering was applied in the discovery set to identify clinical subgroups. The stability of this classification was verified in the validation set. Cranial MRI scans were conducted to compare differences in fractional anisotropy (FA) from diffusion tensor imaging, as well as degree centrality (DC) and regional homogeneity (ReHo) from functional MRI among the different subgroups. Pearson correlation analysis was used to assess the correlations between neuroimaging metrics and scale scores. Results: A total of 154 parents who lost their only child were enrolled, with an average age of (57.6±5.2) years, including 68 males (44.2%), and a mean trauma duration of (15.1±5.1) months. The discovery set and the validation set each comprised 77 participants. Hierarchical clustering and cross-validation consistently identified two stable subgroups. Subgroup A was characterized by core features of traumatic re-experiencing, cognitive avoidance, and depressive mood, while subgroup B was dominated by somatization symptoms and anxiety. Neuroimaging results showed that compared with subgroup B, subgroup A exhibited significantly higher FA values in multiple white matter tracts closely associated with emotion regulation and cognitive processing (P<0.05, corrected with threshold-free cluster enhancement). Compared with subgroup A, subgroup B demonstrated higher DC in the left precentral gyrus (t=-3.02, Gaussian random field-corrected P=0.003) and lower ReHo in the left middle frontal gyrus (t=3.90, Gaussian random field-corrected P=0.001). Correlation analyses indicated that FA values in white matter tracts were positively correlated with total CAPS score, total HAMD-24 score, and specific CAPS factors (avoidance, re-experiencing) (r=0.30-0.36, false discovery rate-corrected P<0.05). DC values in the left precentral gyrus were positively correlated with total HAMA score and the somatic anxiety factor (r=0.32-0.37, false discovery rate-corrected P<0.05). Conclusions: Parents who lost their only child can be categorized into two clinical subgroups: one dominated by emotional disturbances and the other by somatic anxiety. The observed differences in brain structure and function provide neurobiological evidence for this subgroup classification and may suggest potential targets for precise neuromodulation interventions.

Subjective cognitive decline (SCD) may represent a special cognitive stage distinct from mild cognitive impairment (MCI) in Parkinson's disease (PD), but its microstructural correlates are underexplored. We aimed to investigate microstructural alterations in PD-SCD compared to PD with normal cognition (PD-NC) and PD-MCI, and to explore their association with cognitive status. 68 PD patients (PD-NC: n = 23; PD-SCD: n = 20; PD-MCI: n = 25) and 27 healthy controls (HC) underwent multimodal MRI. Analyses included tract-based spatial statistics (TBSS), calculation of the peak width of skeletonized mean diffusivity (PSMD), and hippocampal subfield segmentation. PSMD showed significant differences across subgroups and negatively correlated with MoCA scores, suggesting its utility as a metric that differentiated cognitive stage. TBSS revealed reduced fractional anisotropy (FA) in multiple tracts in PD-MCI, while PD-SCD exhibited reduced FA only in FMajor relative to HC. Hippocampal subfield segmentation revealed atrophy in subregions such as CA1 and HATA in PD-SCD and PD-MCI compared to PD-NC. This study provides evidence that microstructural alterations are already detectable at the PD-SCD stage. PSMD emerges as a sensitive cross-sectional biomarker of PD cognitive staging. These findings highlight the potential role of white‑matter changes in PD‑related cognitive complaints.

The developing hippocampus is particularly sensitive to early environmental influences, including during pregnancy. This longitudinal neuroimaging study examined associations between prenatal maternal physical activity and depression, maternal education, and hippocampal development from early childhood to early adolescence. Participants were mothers and their 113 children (59 females; mean age 4.16±1.25 years at first scan) with 510 magnetic resonance imaging scans. Maternal physical activity and depressive symptoms were assessed during the second trimester. Hippocampal diffusion metrics-including fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD)-as well as volume were measured. Developmental trajectories were analyzed with generalized fractional polynomial mixed models. Results showed significant age-related changes in hippocampal volume and diffusivity, with sex differences in FA development. Bilateral hippocampal volume increased nonlinearly with age, and FA, MD, and RD changed in line with typical brain maturation patterns. However, in contrast to our pre-registered hypotheses, prenatal maternal physical activity was not significantly associated with hippocampal structure. Additionally, in exploratory analyses, we found no significant associations between maternal education or prenatal maternal depression and hippocampal structure. These findings provide a comprehensive characterization of hippocampal development from childhood to adolescence and suggest that prenatal maternal physical activity, depression, and education are not strongly related to hippocampal structure. This work underscores the value of longitudinal neuroimaging and flexible modeling approaches in understanding early brain development.

Individual differences in the structure and function of the frontostriatal reward network have been related to depression. However, there is a strong need for prospective, longitudinal studies aiming to understand the role of frontostriatal networks in depression in a developmental context. We aimed to examine bidirectional associations between structural connectivity in the frontostriatal reward network and depressive symptoms in adolescent girls, as well as to determine to what extent the directionality and strength of these associations are dependent on age or pubertal stage. About 596 observations from 174 adolescent girls (up to 4 time points per person, ages 10-17) were included. Depressive symptoms were measured with the Center for Epidemiological Studies-Depression scale for Children and pubertal stage with the Pubertal Development Scale and the Tanner Stage Line Drawings. Probabilistic tractography was done on diffusion-weighted imaging scans to obtain average fractional anisotropy from ventral striatum to orbitofrontal cortex and ventral striatum to ventromedial prefrontal cortex tracts. Linear mixed-effects models showed that frontostriatal connectivity was not associated with subsequent change in depressive symptoms. Depressive symptoms were also not associated with subsequent change in frontostriatal connectivity. Depressive symptoms increased with age and pubertal stage, but the association with connectivity did not vary with age or pubertal stage. This suggests previously reported cross-sectional associations might not pertain to developmental effects in girls. Future research should examine prospective associations between frontostriatal functional connectivity and depression.

Cerebral white-matter lesions serve as biomarkers for stroke, cardiovascular disease, and mortality. However, no genetic association studies on white-matter hyperintensities (WMH) have focused specifically on the Han Chinese population. Despite previous studies on candidate genes, none have explored association with glucose regulation. This study aimed to investigate the association between a genetic risk score (GRS) derived from glucose-related loci and cerebrovascular abnormality, cerebral WMH, and brain microstructure markers. This study is a community-based family research conducted on 345 participants aged 65 years and over who provided brain magnetic resonance imaging (MRI) examinations and genome-wide association studies data. The volume of white-matter lesions was measured using brain MRI. Generalized linear models with generalized estimating equations were used to analyze the associations between GRSs and brain MRI parameters. Based on the 194 glucose-associated single-nucleotide polymorphisms (SNPs), the GRSs for cerebrovascular abnormality, WMH volume, and fractional anisotropy (FA) and mean diffusivity (MD) for four brain regions, namely, the right and left corticospinal tracts and the cingulate gyri, were calculated based on 3, 3, 10, 5, 8, 6, 8, 8, 9, and 6 significant SNPs. After multivariable adjustment, unweighted and weighted GRS were both associated with cerebrovascular abnormality, WMH volume, FA, and MD of the four sites (right and left corticospinal tracts and cingulate gyri) except for the MD measured using the left cingulate gyrus. Our study indicated that glucose regulation-associated loci are linked to MRI measures, which may provide novel insights into the presence and progression of brain injury.

Determining the biomechanical properties of skeletal muscle in-vivo is challenging due to structural anisotropy. In this study, we developed combined diffusion tensor imaging (DTI) and magnetic resonance elastography (MRE) to quantify direction-dependent biophysical properties of the lower leg muscles and their changes during passive plantarflexion (PF) and dorsiflexion (DF). Thirteen male volunteers were studied using DTI-MRE. Anisotropic shear-wave-speeds parallel (c∥) and perpendicular (c⊥) to the fiber orientation were reconstructed by aligning MRE vector wave fields to the principal fiber axis with rotation angles obtained from DTI tractography. Isotropic ciso was also calculated without rotation for comparison. Fractional anisotropy (FA), radial (RD) and axial diffusivity (AD) were obtained from DTI. c∥ was higher than c⊥ in tibialis anterior (TibA), whereas the opposite was observed in posterior soleus (SolP). From PF to DF, c⊥ and c∥ changed significantly in all muscles: TibA (-15±11%, -15±13%), SolP (8±12%, 9±11%), and gastrocnemius medialis (GasM) (11±15%, 21±14%), respectively (all p<0.05). ciso was only sensitive in TibA (-13±7%) and GasM (4±11%), both p<0.05. For DTI, from PF to DF, FA and RD changed significantly in TibA (-20±12%, 10±7%), SolP (26±12%, -6±6%), and GasM (19±12%, -5±7%), respectively (all p<0.001). AD only changed in SolP (3±5%, p<0.01). In conclusion, anisotropic MRE was more sensitive to ankle positions in lower leg muscles than isotropic MRE and revealed biomechanical differences between muscle types. In the future, DTI-MRE with anisotropic parameter reconstruction could be used for the detection of subtle structural changes in muscle diseases.

Shannon entropy as a stable diffusion tensor parameter for evaluating normal spinal cord regions in dogs.

Background/Objectives: Osmotic demyelination syndrome (ODS) causes marked myelin loss with relative axonal preservation. We used diffusion tensor imaging (DTI) to longitudinally assess white matter (WM) changes, hypothesizing that radial diffusivity (RD) would show dynamic recovery alongside clinical improvement. Methods: A 40-year-old woman with ODS and five age-matched female controls underwent DTI at 7 weeks and 6 months post-onset. Metrics were extracted from 27 WM tract categories using atlas-based regions of interest. Lesions were defined by directional dual thresholds (RD_d ≥ 2.0, axial diffusivity [AD] ≤ -2.0, or fractional anisotropy [FA] ≤ -2.0) and confirmed using the Crawford-Howell test with Benjamini-Hochberg FDR correction (q ≤ 0.05). Longitudinal percent change (Δ%) was compared using the Friedman test with Bonferroni-corrected Wilcoxon post hoc tests (α = 0.017). Results: Serum sodium increased from 126 to 138 mmol/L within 24 h, followed by a severe neurological deficit; near-complete recovery by 6 months. At 7 weeks, RD-defined lesions were detected in 10/27 tracts (37.0%)-1/6 brainstem-related and 9/21 non-brainstem-indicating widespread myelin-predominant injury. No AD- or FA-based lesions met criteria, although AD increase in the cingulate gyrus was significant. From 7 weeks to 6 months, the mean Δ% was -0.40 ± 9.38% (AD), -4.73 ± 9.73% (RD), and +7.94 ± 7.53% (FA). Changes differed across metrics (χ2(2) = 24.07, p = 5.92 × 10-6), with greater RD and FA changes than AD. Conclusions: Early RD-predominant abnormalities preceded RD reduction and FA increase during recovery, consistent with restoration of myelin-related microstructure. Larger studies are warranted.

Cognitive training is a widely recommended technique for cognitive decline and has been shown to improve cognitive functioning. However, the findings on its effect on objective biomarkers of cognitive impairment are highly ambiguous. This study therefore aims to clarify how cognitive training alters brain structure and physiology. A systematic search was conducted in three databases (MEDLINE, Embase, and CENTRAL) for eligible articles in November 2023. The search identified 6.134 articles from which 501 remained after title and abstract selection. Eight articles were identified that assessed the efficacy of cognitive training on objective parameters in non-demented adults. Mean differences (MD) and standardized mean differences (SMD of changes between pre- and post-training data were calculated using random-effects models. 4767 records remained after the removal of duplicates. The selection process ended with 40 eligible articles for qualitative and 8 for quantitative analysis. We did not identify enough articles for the analysis of PET, functional MRI and fluid-based parameters. No significant differences were found in fractional anisotropy (MD=0.01, 95 % Confidence interval (CI): -0.01; 0.04) or in hippocampal volume (SMD=0.03, 95 % CI: -0.01; 0.06). Heterogeneity was high in all analyses. Training groups showed no significant morphological or microstructural modifications compared to control conditions. The current results of objective markers are not powerful enough to recommend cognitive training as a preventive method. Future research should focus on proper randomization, elimination of baseline differences and use standardized techniques. The review was pre-registered with PROSPERO (ID: CRD42023485440).

Interhemispheric auditory tract microstructure in autism spectrum disorder: A diffusion tensor study.