Exploring white matter dynamics and morphology through interactive numerical phantoms: the White Matter Generator.

Brain white matter is a dynamic environment that continuously adapts and reorganizes in response to stimuli and pathological changes. Glial cells, especially, play a key role in tissue repair, inflammation modulation, and neural recovery. The movements of glial cells and changes in their concentrations can influence the surrounding axon morphology. We introduce the White Matter Generator (WMG) tool to enable the study of how axon morphology is influenced through such dynamical processes, and how this, in turn, influences the diffusion-weighted MRI signal. This is made possible by allowing interactive changes to the configuration of the phantom generation throughout the optimization process. The phantoms can consist of myelinated axons, unmyelinated axons, and cell clusters, separated by extra-cellular space. Due to morphological flexibility and computational advantages during the optimization, the tool uses ellipsoids as building blocks for all structures; chains of ellipsoids for axons, and individual ellipsoids for cell clusters. After optimization, the ellipsoid representation can be converted to a mesh representation which can be employed in Monte-Carlo diffusion simulations. This offers an effective method for evaluating tissue microstructure models for diffusion-weighted MRI in controlled bio-mimicking white matter environments. Hence, the WMG offers valuable insights into white matter's adaptive nature and implications for diffusion-weighted MRI microstructure models, and thereby holds the potential to advance clinical diagnosis, treatment, and rehabilitation strategies for various neurological disorders and injuries.

Oligodendroglia and myelin pathology in fragile X syndrome.

Studies of the pathophysiology of fragile X syndrome (FXS) have predominantly focused on synaptic and neuronal disruptions in the disease. However, emerging studies highlight the consistency of white matter abnormalities in the disorder. Recent investigations using animal models of FXS have suggested a role for the fragile X translational regulator 1 protein (FMRP) in the development and function of oligodendrocytes, the myelinating cells of the central nervous system. These studies are starting to uncover FMRP's involvement in the regulation of myelin-related genes, such as myelin basic protein, and its influence on the maturation and functionality of oligodendrocyte precursor cells and oligodendrocytes. Here, we consider evidence of white matter abnormalities in FXS, review our current understanding of FMRP's role in oligodendrocyte development and function, and highlight gaps in our knowledge of the pathogenic mechanisms that may contribute to white matter abnormalities in FXS. Addressing these gaps may help identify new therapeutic strategies aimed at enhancing outcomes for individuals affected by FXS.

Limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) is associated with abnormalities in white matter structural integrity and connectivity: An ex-vivo diffusion MRI and pathology investigation.

Limbic predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) is common in older adults and is associated with neurodegeneration, cognitive decline and dementia. In this MRI and pathology investigation we tested the hypothesis that LATE-NC is associated with abnormalities in white matter structural integrity and connectivity of a network of brain regions typically harboring TDP-43 inclusions in LATE, referred to here as the "LATE-NC network". Ex-vivo diffusion MRI and detailed neuropathological data were collected on 184 community-based older adults. Linear regression revealed an independent association of higher LATE-NC stage with lower diffusion anisotropy in a set of white matter connections forming a pattern of connectivity that is consistent with the stereotypical spread of this pathology in the brain. Graph theory analysis revealed an association of higher LATE-NC stage with weaker integration and segregation in the LATE-NC network. Abnormalities were significant in stage 3, suggesting that they are detectable in later stages of the disease. Finally, LATE-NC network abnormalities were associated with faster cognitive decline, specifically in episodic and semantic memory.

Dynamic monitoring of radiation-induced white matter microstructure injury in nasopharyngeal carcinoma via high-angular resolution diffusion imaging.

PURPOSE: To investigate white matter microstructural abnormalities caused by radiotherapy in nasopharyngeal carcinoma (NPC) patients using MRI high-angular resolution diffusion imaging (HARDI). METHODS: We included 127 patients with pathologically confirmed NPC: 36 in the pre-radiotherapy group, 29 in the acute response period (post-RT-AP), 23 in the early delayed period (post-RT-ED) group, and 39 in the late-delayed period (post-RT-LD) group. HARDI data were acquired for each patient, and dispersion parameters were calculated to compare the differences in specific fibre bundles among the groups. The Montreal Neurocognitive Assessment (MoCA) was used to evaluate neurocognitive function, and the correlations between dispersion parameters and MoCA were analysed. RESULTS: In the right cingulum frontal parietal bundles, the fractional anisotropy value decreased to the lowest level post-RT-AP and then reversed and increased post-RT-ED and post-RT-LD. The mean, axial, and radial diffusivity were significantly increased in the post-RT-AP (p < 0.05) and decreased in the post-RT-ED and post-RT-LD groups to varying degrees. MoCA scores were decreased post-radiotherapy than those before radiotherapy (p = 0.005). MoCA and mean diffusivity exhibited a mild correlation in the left cingulum frontal parahippocampal bundle. CONCLUSIONS: White matter tract changes detected by HARDI are potential biomarkers for monitoring radiotherapy-related brain damage in NPC patients.

Effect of high-fat diet on cerebral pathological changes of cerebral small vessel disease in SHR/SP rats.

Cerebral small vessel diseases (CSVD) are neurological disorders associated with microvessels, manifested pathologically as white matter (WM) changes and cortical microbleeds, with hypertension as a risk factor. Additionally, a high-fat diet (HFD) can affect peripheral vessel health. Our study explored how HFD affects cerebral small vessels in normotensive WKY, hypertensive SHR, and SHR/SP rats. The MRI results revealed that HFD specifically increased WM hyperintensity in SHR/SP rats. Pathologically, it increased WM pallor and vacuolation in SHR and SHR/SP rats. Levels of blood-brain barrier (BBB) protein claudin 5 were decreased in SHR and SHR/SP compared to WKY, with HFD having minimal impact on these levels. Conversely, collagen IV levels remained consistent among the rat strains, which were increased by HFD. Consequently, HFD caused vessel leakage in all rat strains, particularly within the corpus callosum of SHR/SP rats. To understand the underlying mechanisms, we assessed the levels of hypoxia-inducible factor-1α (HIF-1α), Gp91-phox, and neuroinflammatory markers astrocytes, and microglia were increased in SHR and SHR/SP compared to WKY and were further elevated by HFD in all rat strains. Gp91-phox was also increased in SHR and SHR/SP compared to WKY, with HFD causing an increase in WKY but little effect in SHR and SHR/SP. In conclusion, our study demonstrates that HFD, in combined with hypertension, intensifies cerebral pathological alterations in CSVD rats. This exacerbation involves increased oxidative stress and HIF-1α in cerebral vessels, triggering neuroinflammation, vascular basement membrane remodeling, IgG leakage, and ultimately WM damage.

Exercise Improves Cerebral Blood Flow and Functional Outcomes in an Experimental Mouse Model of Vascular Cognitive Impairment and Dementia (VCID).

Vascular cognitive impairment and dementia (VCID) are a growing threat to public health without any known treatment. The bilateral common carotid artery stenosis (BCAS) mouse model is valid for VCID. Previously, we have reported that remote ischemic postconditioning (RIPostC) during chronic cerebral hypoperfusion (CCH) induced by BCAS increases cerebral blood flow (CBF), improves cognitive function, and reduces white matter damage. We hypothesized that physical exercise (EXR) would augment CBF during CCH and prevent cognitive impairment in the BCAS model. BCAS was performed in C57/B6 mice of both sexes to establish CCH. One week after the BCAS surgery, mice were randomized to treadmill exercise once daily or no EXR for four weeks. CBF was monitored with an LSCI pre-, post, and 4 weeks post-BCAS. Cognitive testing was performed for post-BCAS after exercise training, and brain tissue was harvested for histopathology and biochemical test. BCAS led to chronic hypoperfusion resulting in impaired cognitive function and other functional outcomes. Histological examination revealed that BCAS caused changes in neuronal morphology and cell death in the cortex and hippocampus. Immunoblotting showed that BCAS was associated with a significant downregulate of AMPK and pAMPK and NOS3 and pNOS3. BCAS also decreased red blood cell (RBC) deformability. EXR therapy increased and sustained improved CBF and cognitive function, muscular strength, reduced cell death, and loss of white matter. EXR is effective in the BCAS model, improving CBF and cognitive function, reducing white matter damage, improving RBC deformability, and increasing RBC NOS3 and AMPK. The mechanisms by which EXR improves CBF and attenuates tissue damage need further investigation.

Evaluation of white matter microstructural alterations in premature infants with necrotizing enterocolitis.

Background: Preterm infants with necrotizing enterocolitis (NEC) are at high risk of adverse neurodevelopmental outcomes. The aim of this study was to explore the value of diffusion tensor imaging (DTI) combined with serum C-reactive protein (CRP) and procalcitonin (PCT) in evaluating alterations of white matter (WM) microstructure in preterm infants with NEC. Methods: A retrospective cross-sectional study was conducted in which all participants were consecutively enrolled at The Third Affiliated Hospital of Zhengzhou University from June 2017 and October 2021. Data from 30 preterm infants with NEC [mean gestational age at birth 31.41±1.15 weeks; mean age at magnetic resonance imaging (MRI) 37.53±3.08 weeks] and 40 healthy preterm infants with no NEC were recorded (mean gestational age at birth 32.27±2.09 weeks; mean age at MRI 37.15±3.23 weeks). WM was used to obtain the fractional anisotropy (FA) and mean diffusivity (MD) values of the regions of interest (ROIs). Additionally, serum levels of CRP and PCT were determined. Spearman correlation analysis was performed between the WM-derived parameters, CRP level, and the PCT serum index. Results: Preterm infants with NEC had reduced FA values and elevated MD values in WM regions [posterior limbs of the internal capsule (PLIC), lentiform nucleus (LN), frontal white matter (FWM)] compared to the control group (P<0.05). Additionally, the FA of the PLIC was negatively correlated with serum CRP (r=-0.846; P<0.05) and PCT (r=-0.843; P<0.05). Meanwhile, the MD of PLIC was positively correlated with serum CRP (r=0.743; P<0.05) and PCT (r=0.743; P<0.05, respectively). The area under the curve (AUC) of FA and MD combined with CRP and PCT in the diagnosis of WM microstructure alterations with NEC was 0.968, representing a considerable improvement in predicted efficacy over single indicators, including FA [AUC: 0.938; 95% confidence interval (CI): 0.840-0.950], MD (AUC: 0.807; 95% CI: 0.722-0.838), CRP (AUC: 0.867; 95% CI: 0.822-0.889), and PCT (AUC: 0.706; 95% CI: 0.701-0.758). Conclusions: WM can noninvasively and quantitatively assess the WM microstructure alterations in preterm infants with NEC. WM combined with serum CRP and PCT demonstrated superior performance in detecting and evaluating WM microstructure alterations in preterm infants with NEC.

White matter microstructure and connectivity changes after surgery in male adults with obstructive sleep apnea: recovery or reorganization?

Study objectives: Obstructive sleep apnea (OSA) is a prevalent clinical problem significantly affecting cognitive functions. Surgical treatment is recommended for those unable to use continuous positive airway pressure. We aimed to investigate the therapeutic effect of upper airway surgery on the white matter (WM) microstructure and brain connectivity in patients with OSA. Methods: Twenty-one male patients with moderate-to-severe OSA were recruited for multi-level upper airway surgery. Overnight polysomnography (PSG), neuropsychiatric tests, and brain MRI scans were acquired before and 6.1 ± 0.8 months after surgery. Nineteen male patients with untreated OSA were also included as a reference group. We calculated the longitudinal changes of diffusion tensor imaging (DTI) parameters, including fractional anisotropy (ΔFA) and mean/axial/radial diffusivity (ΔMD/AD/RD). We also assessed changes in network properties based on graph theory. Results: Surgically treated patients showed improvement in PSG parameters and verbal memory after surgery. Globally, ΔFA was significantly higher and ΔRD was lower in the surgery group than in the untreated group. Especially ΔFA of the tracts involved in the limbic system was higher after surgery. In network analysis, higher Δbetweenness and lower Δclustering coefficients were observed in the surgical group than in the untreated group. Finally, the improvement of verbal memory after surgery positively correlated with ΔFA in superior thalamic radiation (p = 0.021), fronto aslant tracts (p = 0.027), and forceps minor tracts (p = 0.032). Conclusion: Surgical treatment of OSA can alleviate alterations in WM integrity and disruptions in local networks, particularly for the tracts involved in the limbic system. These findings may further explain the cognitive improvement observed after the treatment of OSA.

Changes in white matter functional networks across late adulthood.

Introduction: The aging brain is characterized by decreases in not only neuronal density but also reductions in myelinated white matter (WM) fibers that provide the essential foundation for communication between cortical regions. Age-related degeneration of WM has been previously characterized by histopathology as well as T2 FLAIR and diffusion MRI. Recent studies have consistently shown that BOLD (blood oxygenation level dependent) effects in WM are robustly detectable, are modulated by neural activities, and thus represent a complementary window into the functional organization of the brain. However, there have been no previous systematic studies of whether or how WM BOLD signals vary with normal aging. We therefore performed a comprehensive quantification of WM BOLD signals across scales to evaluate their potential as indicators of functional changes that arise with aging. Methods: By using spatial independent component analysis (ICA) of BOLD signals acquired in a resting state, WM voxels were grouped into spatially distinct functional units. The functional connectivities (FCs) within and among those units were measured and their relationships with aging were assessed. On a larger spatial scale, a graph was reconstructed based on the pair-wise connectivities among units, modeling the WM as a complex network and producing a set of graph-theoretical metrics. Results: The spectral powers that reflect the intensities of BOLD signals were found to be significantly affected by aging across more than half of the WM units. The functional connectivities (FCs) within and among those units were found to decrease significantly with aging. We observed a widespread reduction of graph-theoretical metrics, suggesting a decrease in the ability to exchange information between remote WM regions with aging. Discussion: Our findings converge to support the notion that WM BOLD signals in specific regions, and their interactions with other regions, have the potential to serve as imaging markers of aging.

Striatal spatial heterogeneity, clustering, and white matter association of GFAP+ astrocytes in a mouse model of Huntington's disease.

Introduction: Huntington's disease (HD) is a neurodegenerative disease that primarily affects the striatum, a brain region that controls movement and some forms of cognition. Neuronal dysfunction and loss in HD is accompanied by increased astrocyte density and astrocyte pathology. Astrocytes are a heterogeneous population classified into multiple subtypes depending on the expression of different gene markers. Studying whether mutant Huntingtin (HTT) alters specific subtypes of astrocytes is necessary to understand their relative contribution to HD. Methods: Here, we studied whether astrocytes expressing two different markers; glial fibrillary acidic protein (GFAP), associated with astrocyte activation, and S100 calcium-binding protein B (S100B), a marker of matured astrocytes and inflammation, were differentially altered in HD. Results: First, we found three distinct populations in the striatum of WT and symptomatic zQ175 mice: GFAP+, S100B+, and dual GFAP+S100B+. The number of GFAP+ and S100B+ astrocytes throughout the striatum was increased in HD mice compared to WT, coinciding with an increase in HTT aggregation. Overlap between GFAP and S100B staining was expected, but dual GFAP+S100B+ astrocytes only accounted for less than 10% of all tested astrocytes and the number of GFAP+S100B+ astrocytes did not differ between WT and HD, suggesting that GFAP+ astrocytes and S100B+ astrocytes are distinct types of astrocytes. Interestingly, a spatial characterization of these astrocyte subtypes in HD mice showed that while S100B+ were homogeneously distributed throughout the striatum, GFAP+ preferentially accumulated in "patches" in the dorsomedial (dm) striatum, a region associated with goal-directed behaviors. In addition, GFAP+ astrocytes in the dm striatum of zQ175 mice showed increased clustering and association with white matter fascicles and were preferentially located in areas with low HTT aggregate load. Discussion: In summary, we showed that GFAP+ and S100B+ astrocyte subtypes are distinctly affected in HD and exist in distinct spatial arrangements that may offer new insights to the function of these specific astrocytes subtypes and their potential implications in HD pathology.

Effect of sex on the APOE4-aging interaction in the white matter microstructure of cognitively normal older adults using diffusion-tensor MRI with orthogonal-tensor decomposition (DT-DOME).

The influence of the apolipoprotein E ε4 allele (APOE4) on brain microstructure of cognitively normal older adults remains incompletely understood, in part due to heterogeneity within study populations. In this study, we examined white-matter microstructural integrity in cognitively normal older adults as a function of APOE4 carrier status using conventional diffusion-tensor imaging (DTI) and the novel orthogonal-tensor decomposition (DT-DOME), accounting for the effects of age and sex. Age associations with white-matter microstructure did not significantly depend on APOE4 status, but did differ between sexes, emphasizing the importance of accounting for sex differences in APOE research. Moreover, we found the DT-DOME to be more sensitive than conventional DTI metrics to such age-related and sex effects, especially in crossing WM fiber regions, and suggest their use in further investigation of white matter microstructure across the life span in health and disease.

Stability of longitudinal DTI metrics in MS with treatment of injectables, fingolimod and dimethyl fumarate.

BACKGROUND AND PURPOSE: Diffusion MRI (dMRI) is sensitive to microstructural changes in white matter of people with relapse-remitting multiple sclerosis (pw-RRMS) that lead to progressive disability. The role of diffusion in assessing the efficacy of different therapies requires more investigation. This study aimed to evaluate selected dMRI metrics in normal-appearing white matter and white matter-lesion in pw-RRMS and healthy controls longitudinally and compare the effect of therapies given. MATERIAL AND METHODS: Structural and dMRI scans were acquired from 78 pw-RRMS (29 injectables, 36 fingolimod, 13 dimethyl fumarate) and 43 HCs at baseline and 2-years follow-up. Changes in dMRI metrics and correlation with clinical parameters were evaluated. RESULTS: Differences were observed in most clinical parameters between pw-RRMS and HCs at both timepoints (p ≤ 0.01). No significant differences in average changes over time were observed for any dMRI metric between treatment groups in either tissue type. Diffusion metrics in NAWM and WML correlated negatively with most cognitive domains, while FA correlated positively at baseline but only for NAWM at follow-up (p ≤ 0.05). FA correlated negatively with disability in NAWM and WML over time, while MD and RD correlated positively only in NAWM. CONCLUSIONS: This is the first DTI study comparing the effect of different treatments on dMRI parameters over time in a stable cohort of pw-RRMS. The results suggest that brain microstructural changes in a stable MS cohort are similar to HCs independent of the therapies used.

White matter alterations in drug-naïve children with Tourette syndrome and obsessive-compulsive disorder.

Tourette syndrome (TS) and early-onset obsessive-compulsive disorder (OCD) are frequently associated and conceptualized as distinct phenotypes of a common disease spectrum. However, the nature of their relationship is still largely unknown on a pathophysiological level. In this study, early structural white matter (WM) changes investigated through diffusion tensor imaging (DTI) were compared across four groups of drug-naïve children: TS-pure (n = 16), TS+OCD (n = 14), OCD (n = 10), and 11 age-matched controls. We analyzed five WM tracts of interest, i.e., cortico-spinal tract (CST), anterior thalamic radiations (ATR), inferior longitudinal fasciculus (ILF), corpus callosum (CC), and cingulum and evaluated correlations of DTI changes to symptom severity. Compared to controls, TS-pure and TS+OCD showed a comparable pattern of increased fractional anisotropy (FA) in CST, ATR, ILF and CC, with FA changes displaying negative correlation to tic severity. Conversely, in OCD, FA decreased in all WM tracts (except for the cingulum) compared to controls and negatively correlated to symptoms. We demonstrate different early WM microstructural alterations in children with TS-pure/TS+OCD as opposed to OCD. Our findings support the conceptualization of TS+OCD as a subtype of TS while suggesting that OCD is characterized by independent pathophysiological mechanisms affecting WM development.

Individual differences in slow wave sleep architecture relate to variation in white matter microstructure across adulthood.

Sleep plays a key role in supporting brain function and resilience to brain decline. It is well known that sleep changes substantially with aging and that aging is associated with deterioration of brain structure. In this study, we sought to characterize the relationship between slow wave slope (SWslope)-a key marker of sleep architecture and an indirect proxy of sleep quality-and microstructure of white matter pathways in healthy adults with no sleep complaints. Participants were 12 young (24-27 years) and 12 older (50-79 years) adults. Sleep was assessed with nocturnal electroencephalography (EEG) and the Pittsburgh Sleep Quality Index (PSQI). White matter integrity was assessed using tract-based spatial statistics (TBSS) on tensor-based metrics such as Fractional Anisotropy (FA) and Mean Diffusivity (MD). Global PSQI score did not differ between younger (n = 11) and older (n = 11) adults (U = 50, p = 0.505), but EEG revealed that younger adults had a steeper SWslope at both frontal electrode sites (F3: U = 2, p < 0.001, F4: U = 4, p < 0.001, n = 12 younger, 10 older). There were widespread correlations between various diffusion tensor-based metrics of white matter integrity and sleep SWslope, over and above effects of age (n = 11 younger, 9 older). This was particularly evident for the corpus callosum, corona radiata, superior longitudinal fasciculus, internal and external capsule. This indicates that reduced sleep slow waves may be associated with widespread white matter deterioration. Future studies should investigate whether interventions targeted at improving sleep architecture also impact on decline in white matter microstructure in older adults.

Chronic anemia: The effects on the connectivity of white matter.

Chronic anemia is commonly observed in patients with hemoglobinopathies, mainly represented by disorders of altered hemoglobin (Hb) structure (sickle cell disease, SCD) and impaired Hb synthesis (e.g. thalassemia syndromes, non-SCD anemia). Both hemoglobinopathies have been associated with white matter (WM) alterations. Novel structural MRI research in our laboratory demonstrated that WM volume was diffusely lower in deep, watershed areas proportional to anemia severity. Furthermore, diffusion tensor imaging analysis has provided evidence that WM microstructure is disrupted proportionally to Hb level and oxygen saturation. SCD patients have been widely studied and demonstrate lower fractional anisotropy (FA) in the corticospinal tract and cerebellum across the internal capsule and corpus callosum. In the present study, we compared 19 SCD and 15 non-SCD anemia patients with a wide range of Hb values allowing the characterization of the effects of chronic anemia in isolation of sickle Hb. We performed a tensor analysis to quantify FA changes in WM connectivity in chronic anemic patients. We calculated the volumetric mean of FA along the pathway of tracks connecting two regions of interest defined by BrainSuite's BCI-DNI atlas. In general, we found lower FA values in anemic patients; indicating the loss of coherence in the main diffusion direction that potentially indicates WM injury. We saw a positive correlation between FA and hemoglobin in these same regions, suggesting that decreased WM microstructural integrity FA is highly driven by chronic hypoxia. The only connection that did not follow this pattern was the connectivity within the left middle-inferior temporal gyrus. Interestingly, more reductions in FA were observed in non-SCD patients (mainly along with intrahemispheric WM bundles and watershed areas) than the SCD patients (mainly interhemispheric).

Emerging cellular themes in leukodystrophies.

Leukodystrophies are a broad spectrum of neurological disorders that are characterized primarily by deficiencies in myelin formation. Clinical manifestations of leukodystrophies usually appear during childhood and common symptoms include lack of motor coordination, difficulty with or loss of ambulation, issues with vision and/or hearing, cognitive decline, regression in speech skills, and even seizures. Many cases of leukodystrophy can be attributed to genetic mutations, but they have diverse inheritance patterns (e.g., autosomal recessive, autosomal dominant, or X-linked) and some arise from de novo mutations. In this review, we provide an updated overview of 35 types of leukodystrophies and focus on cellular mechanisms that may underlie these disorders. We find common themes in specialized functions in oligodendrocytes, which are specialized producers of membranes and myelin lipids. These mechanisms include myelin protein defects, lipid processing and peroxisome dysfunction, transcriptional and translational dysregulation, disruptions in cytoskeletal organization, and cell junction defects. In addition, non-cell-autonomous factors in astrocytes and microglia, such as autoimmune reactivity, and intercellular communication, may also play a role in leukodystrophy onset. We hope that highlighting these themes in cellular dysfunction in leukodystrophies may yield conceptual insights on future therapeutic approaches.

Associations of cardiorespiratory fitness and exercise with brain white matter in healthy adults: A systematic review and meta-analysis.

Magnetic resonance imaging (MRI) studies have revealed positive associations between brain structure and physical activity, cardiorespiratory fitness, and exercise (referred to here as PACE). While a considerable body of research has investigated the effects of PACE on grey matter, much less is known about effects on white matter (WM). Hence, we conducted a systematic review of peer-reviewed literature published prior to 5th July 2021 using online databases (PubMed and Scopus) and PRISMA guidelines to synthesise what is currently known about the relationship between PACE and WM in healthy adults. A total of 60 studies met inclusion criteria and were included in the review. Heterogeneity across studies was calculated using Qochran's q test, and publication bias was assessed for each meta-analysis using Begg and Mazumdar rank correlation test. A meta-regression was also conducted to explore factors contributing to any observed heterogeneity. Overall, we observed evidence of positive associations between PACE and global WM volume (effect size (Hedges's g) = 0.137, p < 0.001), global WM anomalies (effect size = 0.182, p < 0.001), and local microstructure integrity (i.e., corpus callosum: effect size = 0.345, p < 0.001, and anterior limb of internal capsule: effect size = 0.198, p < 0.001). These findings suggest that higher levels of PACE are associated with improved global WM volume and local integrity. We appraise the quality of evidence, and discuss the implications of these findings for the preservation of WM across the lifespan. We conclude by providing recommendations for future research in order to advance our understanding of the specific PACE parameters and neurobiological mechanisms underlying these effects.

Post-Stroke Administration of L-4F Promotes Neurovascular and White Matter Remodeling in Type-2 Diabetic Stroke Mice.

Patients with type 2 diabetes mellitus (T2DM) exhibit a distinct and high risk of ischemic stroke with worse post-stroke neurovascular and white matter (WM) prognosis than the non-diabetic population. In the central nervous system, the ATP-binding cassette transporter member A 1 (ABCA1), a reverse cholesterol transporter that efflux cellular cholesterol, plays an important role in high-density lipoprotein (HDL) biogenesis and in maintaining neurovascular stability and WM integrity. Our previous study shows that L-4F, an economical apolipoprotein A member I (ApoA-I) mimetic peptide, has neuroprotective effects via alleviating neurovascular and WM impairments in the brain of db/db-T2DM stroke mice. To further investigate whether L-4F has neurorestorative benefits in the ischemic brain after stroke in T2DM and elucidate the underlying molecular mechanisms, we subjected middle-aged, brain-ABCA1 deficient (ABCA1-B/-B), and ABCA1-floxed (ABCA1fl/fl) T2DM control mice to distal middle cerebral artery occlusion. L-4F (16 mg/kg, subcutaneous) treatment was initiated 24 h after stroke and administered once daily for 21 days. Treatment of T2DM-stroke with L-4F improved neurological functional outcome, and decreased hemorrhage, mortality, and BBB leakage identified by decreased albumin infiltration and increased tight-junction and astrocyte end-feet densities, increased cerebral arteriole diameter and smooth muscle cell number, and increased WM density and oligodendrogenesis in the ischemic brain in both ABCA1-B/-B and ABCA1fl/fl T2DM-stroke mice compared with vehicle-control mice, respectively (p < 0.05, n = 9 or 21/group). The L-4F treatment reduced macrophage infiltration and neuroinflammation identified by decreases in ED-1, monocyte chemoattractant protein-1 (MCP-1), and toll-like receptor 4 (TLR4) expression, and increases in anti-inflammatory factor Insulin-like growth factor 1 (IGF-1) and its receptor IGF-1 receptor ß (IGF-1Rß) in the ischemic brain (p < 0.05, n = 6/group). These results suggest that post-stroke administration of L-4F may provide a restorative strategy for T2DM-stroke by promoting neurovascular and WM remodeling. Reducing neuroinflammation in the injured brain may contribute at least partially to the restorative effects of L-4F independent of the ABCA1 signaling pathway.

Separating Glioma Hyperintensities From White Matter by Diffusion-Weighted Imaging With Spherical Tensor Encoding.

Background: Tumor-related hyperintensities in high b-value diffusion-weighted imaging (DWI) are radiologically important in the workup of gliomas. However, the white matter may also appear as hyperintense, which may conflate interpretation. Purpose: To investigate whether DWI with spherical b-tensor encoding (STE) can be used to suppress white matter and enhance the conspicuity of glioma hyperintensities unrelated to white matter. Materials and Methods: Twenty-five patients with a glioma tumor and at least one pathology-related hyperintensity on DWI underwent conventional MRI at 3 T. The DWI was performed both with linear and spherical tensor encoding (LTE-DWI and STE-DWI). The LTE-DWI here refers to the DWI obtained with conventional diffusion encoding and averaged across diffusion-encoding directions. Retrospectively, the differences in contrast between LTE-DWI and STE-DWI, obtained at a b-value of 2,000 s/mm2, were evaluated by comparing hyperintensities and contralateral normal-appearing white matter (NAWM) both visually and quantitatively in terms of the signal intensity ratio (SIR) and contrast-to-noise ratio efficiency (CNReff). Results: The spherical tensor encoding DWI was more effective than LTE-DWI at suppressing signals from white matter and improved conspicuity of pathology-related hyperintensities. The median SIR improved in all cases and on average by 28%. The median (interquartile range) SIR was 1.9 (1.6 - 2.1) for STE and 1.4 (1.3 - 1.7) for LTE, with a significant difference of 0.4 (0.3 -0.5) (p < 10-4, paired U-test). In 40% of the patients, the SIR was above 2 for STE-DWI, but with LTE-DWI, the SIR was below 2 for all patients. The CNReff of STE-DWI was significantly higher than of LTE-DWI: 2.5 (2 - 3.5) vs. 2.3 (1.7 - 3.1), with a significant difference of 0.4 (-0.1 -0.6) (p < 10-3, paired U-test). The STE improved CNReff in 70% of the cases. We illustrate the benefits of STE-DWI in three patients, where STE-DWI may facilitate an improved radiological description of tumor-related hyperintensity, including one case that could have been missed out if only LTE-DWI was inspected. Conclusion: The contrast mechanism of high b-value STE-DWI results in a stronger suppression of white matter than conventional LTE-DWI, and may, therefore, be more sensitive and specific for assessment of glioma tumors and DWI-hyperintensities.