Bruton's tyrosine kinase inhibition ameliorated neuroinflammation during chronic white matter ischemia.

Chronic cerebral hypoperfusion (CCH), a disease afflicting numerous individuals worldwide, is a primary cause of cognitive deficits, the pathogenesis of which remains poorly understood. Bruton's tyrosine kinase inhibition (BTKi) is considered a promising strategy to regulate inflammatory responses within the brain, a crucial process that is assumed to drive ischemic demyelination progression. However, the potential role of BTKi in CCH has not been investigated so far. In the present study, we elucidated potential therapeutic roles of BTK in both in vitro hypoxia and in vivo ischemic demyelination model. We found that cerebral hypoperfusion induced white matter injury, cognitive impairments, microglial BTK activation, along with a series of microglia responses associated with inflammation, oxidative stress, mitochondrial dysfunction, and ferroptosis. Tolebrutinib treatment suppressed both the activation of microglia and microglial BTK expression. Meanwhile, microglia-related inflammation and ferroptosis processes were attenuated evidently, contributing to lower levels of disease severity. Taken together, BTKi ameliorated white matter injury and cognitive impairments induced by CCH, possibly via skewing microglia polarization towards anti-inflammatory and homeostatic phenotypes, as well as decreasing microglial oxidative stress damage and ferroptosis, which exhibits promising therapeutic potential in chronic cerebral hypoperfusion-induced demyelination.

ω-3 PUFA for Secondary Prevention of White Matter Lesions and Neuronal Integrity Breakdown in Older Adults: A Randomized Clinical Trial.

Importance: Older adults with lower intake and tissue levels of long-chain ω-3 polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid (EPA; 20:5) and docosahexaenoic acid (DHA; 22:6) have more brain white matter lesions (WMLs), an association suggesting that small-vessel ischemic disease, a major contributor to the development of dementia, including Alzheimer disease, may be preventable through ω-3 treatment. Objective: To determine whether ω-3 treatment reduces WML accumulation in older adults without dementia harboring WMLs and with suboptimal ω-3 status. Design, Setting, and Participants: This quadruple-blinded, placebo-controlled, randomized clinical trial with treatment stratification by apolipoprotein E ε4 allele (APOE*E4) carrier status used linear mixed-effects models to estimate mean annual change between groups. The study was conducted at Oregon Health & Science University, a major academic medical center in the Pacific Northwest, from May 2014 to final participant visit in September 2019. Data analysis concluded in July 2022. Participants were adults without dementia aged 75 years and older with WMLs greater than or equal to 5 cm3 and plasma ω-3 PUFA less than 5.5 weight percentage of total. Intervention: Three-year treatment with 1.65 g of ω-3 PUFA (975 mg of EPA and 650 mg of DHA) vs a soybean oil placebo matched for taste, smell, and appearance. Main Outcomes and Measures: The primary outcome was annual WML progression measured using magnetic resonance imaging. Secondary outcomes included diffusion tensor imaging of fractional anisotropy (DTI-FA), representing neuronal integrity breakdown. Results: A total of 102 participants (62 women [60.8%]; mean age, 81 years [range, 75-96 years]) were equally randomized, 51 per treatment group. Although the ω-3 group had less annual WML accumulation than the placebo group, the difference was not statistically significant (1.19 cm3 [95% CI, 0.64-1.74 cm3] vs 1.34 cm3 [95% CI, 0.80-1.88 cm3]; P = .30). Similarly, the ω-3 group had less annual DTI-FA decline than the placebo group, but the difference was not statistically significant (-0.0014 mm2/s [95% CI, -0.0027 to 0.0002 mm2/s] vs -0.0027 mm2/s [95% CI, -0.0041 to -0.0014 mm2/s]; P = .07). Among APOE*E4 carriers, the annual DTI-FA decline was significantly lower in the group treated with ω-3 than the placebo group (-0.0016 mm2/s [95% CI, -0.0032 to 0.0020 mm2/s] vs -0.0047 mm2/s [95% CI, -0.0067 to -0.0025 mm2/s]; P = .04). Adverse events were similar between treatment groups. Conclusions and Relevance: In this 3-year randomized clinical trial, ω-3 treatment was safe and well-tolerated but failed to reach significant reductions in WML accumulation or neuronal integrity breakdown among all participants, which may be attributable to sample size limitations. However, neuronal integrity breakdown was reduced by ω-3 treatment in APOE*E4 carriers, suggesting that this treatment may be beneficial for this specific group. Trial Registration: ClinicalTrials.gov Identifier: NCT01953705.

Greater White Matter Hyperintensity Volume Is Associated with the Number of Microhemorrhages in Preclinical Alzheimer's Disease.

BACKGROUND: Increased white matter hyperintensity (WMH) volume visible on MRI is a common finding in Alzheimer's disease (AD). We hypothesized that WMH in preclinical AD is associated with the presence of advanced vessel amyloidosis manifested as microhemorrhages (MCH). OBJECTIVES: 1) To assess the relationship between baseline WMH volume and baseline MCH. 2) To assess the relationship between longitudinal WMH accumulation and last MRI MCH during the double-blind phase of the A4 trial. DESIGN: A multicenter, randomized, double-blind, placebo-controlled, Phase 3 study comparing solanezumab with placebo given as infusions once every 4 weeks over 4.5 years in subjects with preclinical AD, defined as having evidence of elevated brain amyloid before the stage of clinically evident cognitive impairment, with an optional open-label extension period. SETTING: Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study. PARTICIPANTS: A sample of 1157 cognitively unimpaired older adults (mean age = 71.9 years [SD = 4.8 years], 59% women, 59% APOE ε4 carriers). MEASUREMENTS: A linear regression model was used to assess the impact of baseline MCH amount (0, 1, 2+) on WMH volume. A linear mixed-effects model was used to assess the impact of last MRI MCH on longitudinal WMH. All models were corrected for age, sex, grey matter volume, cortical amyloid PET, APOE ε4 status, and treatment group. RESULTS: Baseline WMH volume was greater in individuals with more than one MCH compared to those with no MCH (t=4.8, p<0.001). The longitudinal increase in WMH amongst individuals with one (t=2.3, p=0.025) and more than one MCH (t=6.7, p<0.001) at the last MRI was greater than those with no MCH. CONCLUSION: These results indicate a strong association between WMH and MCH, a common manifestation of cerebral amyloid angiopathy and ARIA-H. These results suggest that increased WMH volume may represent an early sign of vessel amyloidosis, likely prior to the emergence of MCH.

NKCC1 inhibition reduces periaxonal swelling, increases white matter sparing, and improves neurological recovery after contusive SCI.

Ultrastructural studies of contusive spinal cord injury (SCI) in mammals have shown that the most prominent acute changes in white matter are periaxonal swelling and separation of myelin away from their axon, axonal swelling, and axonal spheroid formation. However, the underlying cellular and molecular mechanisms that cause periaxonal swelling and the functional consequences are poorly understood. We hypothesized that periaxonal swelling and loss of connectivity between the axo-myelinic interface impedes neurological recovery by disrupting conduction velocity, and glial to axonal trophic support resulting in axonal swelling and spheroid formation. Utilizing in vivo longitudinal imaging of Thy1YFP+ axons and myelin labeled with Nile red, we reveal that periaxonal swelling significantly increases acutely following a contusive SCI (T13, 30 kdyn, IH Impactor) versus baseline recordings (laminectomy only) and often precedes axonal spheroid formation. In addition, using longitudinal imaging to determine the fate of myelinated fibers acutely after SCI, we show that ∼73% of myelinated fibers present with periaxonal swelling at 1 h post SCI and âˆ¼ 51% of those fibers transition to axonal spheroids by 4 h post SCI. Next, we assessed whether cation-chloride cotransporters present within the internode contributed to periaxonal swelling and whether their modulation would increase white matter sparing and improve neurological recovery following a moderate contusive SCI (T9, 50 kdyn). Mechanistically, activation of the cation-chloride cotransporter KCC2 did not improve neurological recovery and acute axonal survival, but did improve chronic tissue sparing. In distinction, the NKKC1 antagonist bumetanide improved neurological recovery, tissue sparing, and axonal survival, in part through preventing periaxonal swelling and disruption of the axo-myelinic interface. Collectively, these data reveal a novel neuroprotective target to prevent periaxonal swelling and improve neurological recovery after SCI.

N-butyl-ß-carboline-3-carboxylate (ß-CCB) systemic administration promotes remyelination in the cuprizone demyelinating model in mice.

Demyelination is generated in several nervous system illnesses. Developing strategies for effective clinical treatments requires the discovery of promyelinating drugs. Increased GABAergic signaling through γ-aminobutyric acid type A receptor (GABAAR) activation in oligodendrocytes has been proposed as a promyelinating condition. GABAAR expressed in oligodendroglia is strongly potentiated by n-butyl-ß-carboline-3-carboxylate (ß-CCB) compared to that in neurons. Here, mice were subjected to 0.3% cuprizone (CPZ) added in the food to induce central nervous system demyelination, a well-known model for multiple sclerosis. Then ß-CCB (1 mg/Kg) was systemically administered to analyze the remyelination status in white and gray matter areas. Myelin content was evaluated using Black-Gold II (BGII) staining, immunofluorescence (IF), and magnetic resonance imaging (MRI). Evidence indicates that ß-CCB treatment of CPZ-demyelinated animals promoted remyelination in several white matter structures, such as the fimbria, corpus callosum, internal capsule, and cerebellar peduncles. Moreover, using IF, it was observed that CPZ intake induced an increase in NG2+ and a decrease in CC1+ cell populations, alterations that were importantly retrieved by ß-CCB treatment. Thus, the promyelinating character of ß-CCB was confirmed in a generalized demyelination model, strengthening the idea that it has clinical potential as a therapeutic drug.

Longitudinal alcohol-related brain changes in older adults: The Sydney Memory and Ageing Study.

Increases in harmful drinking among older adults indicate the need for a more thorough understanding of the relationship between later-life alcohol use and brain health. The current study investigated the relationships between alcohol use and progressive grey and white matter changes in older adults using longitudinal data. A total of 530 participants (aged 70 to 90 years; 46.0% male) were included. Brain outcomes assessed over 6 years included total grey and white matter volume, as well as volume of the hippocampus, thalamus, amygdala, corpus callosum, orbitofrontal cortex and insula. White matter integrity was also investigated. Average alcohol use across the study period was the main exposure of interest. Past-year binge drinking and reduction in drinking from pre-baseline were additional exposures of interest. Within the context of low-level average drinking (averaging 11.7 g per day), higher average amount of alcohol consumed was associated with less atrophy in the left (B = 7.50, pFDR = 0.010) and right (B = 5.98, pFDR = 0.004) thalamus. Past-year binge-drinking was associated with poorer white matter integrity (B = -0.013, pFDR = 0.024). Consuming alcohol more heavily in the past was associated with greater atrophy in anterior (B = -12.73, pFDR = 0.048) and posterior (B = -17.88, pFDR = 0.004) callosal volumes over time. Across alcohol exposures and neuroimaging markers, no other relationships were statistically significant. Within the context of low-level drinking, very few relationships between alcohol use and brain macrostructure were identified. Meanwhile, heavier drinking was negatively associated with white matter integrity.

Berberine improves cognitive impairment by alleviating brain atrophy and promoting white matter reorganization in diabetic db/db mice: a magnetic resonance imaging-based study.

Diabetic cognitive impairment is a common complication in type 2 diabetes. Berberine (BBR) is an isoquinoline alkaloid that has been shown to have neuroprotective effects against diabetes. This study aimed to investigate the effect of BBR on the gray and white matter of the brain by using magnetic resonance imaging (MRI) and to explore the underlying mechanisms. The study used diabetic db/db mice and administered BBR (50 and 100 mg/kg) intragastrically for twelve weeks. Morris water maze was applied to examine cognitive function. T2-weighted imaging (T2WI) was performed to assess brain atrophy, and diffusion tensor imaging (DTI) combined with fiber tracking was conducted to monitor the structural integrity of the white matter, followed by histological immunostaining. Furthermore, the protein expressions of the phosphatidylinositol 3-kinase (PI3K)/ protein kinase B (AKT)/ glycogen synthase kinase-3ß (GSK-3ß) were detected. The results revealed that BBR significantly improved the spatial learning and memory of the db/db mice. T2WI exhibited ameliorated brain atrophy in the BBR-treated db/db mice, as evidenced by reduced ventricular volume accompanied by increased hippocampal volumes. DTI combined with fiber tracking revealed that BBR increased FA, fiber density and length in the corpus callosum/external capsule of the db/db mice. These imaging findings were confirmed by histological immunostaining. Notably, BBR significantly enhanced the protein levels of phosphorylated AKT at Ser473 and GSK-3ß at Ser9. Collectively, this study demonstrated that BBR significantly improved the cognitive function of the diabetic db/db mice through ameliorating brain atrophy and promoting white matter reorganization via AKT/GSK-3ß pathway.

Prescription Opioids and Brain Structure in Community-Dwelling Older Adults.

OBJECTIVE: To evaluate the associations between prescription opioid exposures in community-dwelling older adults and gray and white matter structure by magnetic resonance imaging. METHODS: Secondary analysis was conducted of a prospective, longitudinal population-based cohort study employing cross-sectional imaging of older adult (≥65 years) enrollees between November 1, 2004, and December 31, 2017. Gray matter outcomes included cortical thickness in 41 structures and subcortical volumes in 6 structures. White matter outcomes included fractional anisotropy in 40 tracts and global white matter hyperintensity volumes. The primary exposure was prescription opioid availability expressed as the per-year rate of opioid days preceding magnetic resonance imaging, with a secondary exposure of per-year total morphine milligram equivalents (MME). Multivariable models assessed associations between opioid exposures and brain structures. RESULTS: The study included 2185 participants; median (interquartile range) age was 80 (75 to 85) years, 47% were women, and 1246 (57%) received opioids. No significant associations were found between opioids and gray matter. Increased opioid days and MME were associated with decreased white matter fractional anisotropy in 15 (38%) and 16 (40%) regions, respectively, including the corpus callosum, posterior thalamic radiation, and anterior limb of the internal capsule, among others. Opioid days and MME were also associated with greater white matter hyperintensity volume (1.02 [95% CI, 1.002 to 1.036; P=.029] and 1.01 [1.001 to 1.024; P=.032] increase in the geometric mean, respectively). CONCLUSION: The duration and dose of prescription opioids were associated with decreased white matter integrity but not with gray matter structure. Future studies with longitudinal imaging and clinical correlation are warranted to further evaluate these relationships.

Inhibition of ADORA3 promotes microglial phagocytosis and alleviates chronic ischemic white matter injury.

BACKGROUND: Adenosine A3 receptor (ADORA3) belongs to the adenosine receptor families and the role of ADORA3 in vascular dementia (VaD) is largely unexplored. The present study sought to determine the therapeutic role of ADORA3 antagonist in a mouse model of VaD. METHODS: The GSE122063 dataset was selected to screen the differential expression genes and pathways between VaD patients and controls. A mouse model of bilateral carotid artery stenosis (BCAS) was established. The cognitive functions were examined by the novel object recognition test, Y maze test, and fear of conditioning test. The white matter injury (WMI) was examined by 9.4 T MRI, western blot, and immunofluorescence staining. The mechanisms of ADORA3-regulated phagocytosis by microglia were examined using qPCR, western blot, dual immunofluorescence staining, and flow cytometry. RESULTS: The expression of ADORA3 was elevated in brain tissues of VaD patients and ADORA3 was indicated as a key gene for VaD in the GSE122063. In BCAS mice, the expression of ADORA3 was predominantly elevated in microglia in the corpus callosum. ADORA3 antagonist promotes microglial phagocytosis to myelin debris by facilitating cAMP/PKA/p-CREB pathway and thereby ameliorates WMI and cognitive impairment in BCAS mice. The therapeutic effect of ADORA3 antagonist was partially reversed by the inhibition of the cAMP/PKA pathway. CONCLUSIONS: ADORA3 antagonist alleviates chronic ischemic WMI by modulating myelin clearance of microglia, which may be a potential therapeutic target for the treatment of VaD.

Decoupling of gray and white matter functional networks in cognitive impairment induced by occupational aluminum exposure.

Aluminum (Al) is a low-toxic, accumulative substance with neurotoxicity properties that adversely affect human cognitive function. This study aimed to investigate the neurobiological mechanisms underlying cognitive impairment resulting from occupational Al exposure. Resting-state functional magnetic resonance imaging was conducted on 54 individuals with over 10 years of Al exposure. Al levels were measured, and cognitive function was assessed using the Montreal Cognitive Assessment (MoCA). Subsequently, the K-means clustering algorithm was employed to identify functional gray matter (GM) and white matter (WM) networks. Two-sample t-tests were conducted between the cognition impairment group and the control group. Al exhibited a negative correlation with MoCA scores. Participants with cognitive impairment demonstrated reduced functional connectivity (FC) between the middle cingulum network (WM1) and anterior cingulum network (WM2), as well as between the executive control network (WM6) and limbic network (WM10). Notably, decreased FCs were observed between the executive control network (GM5) and WM1, WM4, WM6, and WM10. Additionally, the FC of GM5-GM4 and WM1-WM2 negatively correlated with Trail Making Test Part A (TMT-A) scores. Prolonged Al accumulation detrimentally affects cognition, primarily attributable to executive control and limbic network disruptions.

ISRIB improves white matter injury following TBI by inhibiting NCOA4-mediated ferritinophagy.

Traumatic brain injury (TBI) often results in persistent neurological dysfunction, which is closely associated with white matter injury. The mechanisms underlying white matter injury after TBI remain unclear. Ferritinophagy is a selective autophagic process that degrades ferritin and releases free iron, which may cause ferroptosis. Although ferroptosis has been demonstrated to be involved in TBI, it is unclear whether ferritinophagy triggers ferroptosis in TBI. Integrated stress response inhibitor (ISRIB) has neuroprotective properties. However, the effect of ISRIB on white matter after TBI remains uncertain. We aimed to investigate whether ferritinophagy was involved in white matter injury following TBI and whether ISRIB can mitigate white matter injury after TBI by inhibiting ferritinophagy. In this study, controlled cortical impact (CCI) was performed on rats to establish the TBI model. Ferritinophagy was measured by assessing the levels of nuclear receptor coactivator 4 (NCOA4), which regulates ferritinophagy, ferritin heavy chain 1(FTH1), LC3, ATG5, and FTH1 colocalization with LC3 in the white matter. Increased NCOA4 and decreased FTH1 were detected in our study. FTH1 colocalization with LC3 enhanced in the white matter after TBI, indicating that ferritinophagy was activated. Immunofluorescence co-localization results also suggested that ferritinophagy occurred in neurons and oligodendrocytes after TBI. Furthermore, ferroptosis was assessed by determining free iron content, MDA content, GSH content, and Perl's staining. The results showed that ferroptosis was suppressed by NCOA4 knockdown via shNCOA4 lentivirus infection, indicating that ferroptosis in TBI is triggered by ferritinophagy. Besides, NCOA4 deletion notably improved white matter injury following TBI, implying that ferritinophagy contributed to white matter injury. ISRIB treatment reduced the occurrence of ferritinophagy in neurons and oligodendrocytes, attenuated ferritinophagy-induced ferroptosis, and alleviated white matter injury. These findings suggest that NCOA4-mediated ferritinophagy is a critical mechanism underlying white matter injury after TBI. ISRIB holds promise as a therapeutic agent for this condition.

Positive Effects of Uric Acid on White Matter Microstructures and Treatment Response in Patients With Schizophrenia.

BACKGROUND AND HYPOTHESIS: Schizophrenia involves microstructural changes in white matter (WM) tracts. Oxidative stress is a key factor causing WM damage by hindering oligodendrocyte development and myelin maturation. Uric acid (UA), an endogenous antioxidant, may protect against oxidative stress. We investigated the effect of UA on WM connectivity in antipsychotic-naive or -free patients with early- or chronic-stage schizophrenia. STUDY DESIGN: A total of 192 patients with schizophrenia (122 recent-onset [ROS] and 70 chronic [CS]) and 107 healthy controls (HCs) participated in this study. Diffusion tensor imaging data and serum UA levels at baseline were obtained. STUDY RESULTS: Fractional anisotropy was lower in the widespread WM regions across the whole brain, and diffusivity measures were higher in both schizophrenia groups than in HCs. The CS group showed lower diffusivity in some WM tracts than the ROS or HC groups. The linear relationship of serum UA levels with axial and mean diffusivity in the right frontal region was significantly different between schizophrenia stages, which was driven by a negative association in the CS group. WM diffusivity associated with serum UA levels correlated with 8-week treatment responses only in patients with CS, suggesting UA to be protective against long-term schizophrenia. CONCLUSIONS: UA may protect against the WM damage associated with the progression of schizophrenia by reducing oxidative stress and supporting WM repair against oxidative damage. These results provide insights into the positive role of UA and may facilitate the development of novel disease-modifying therapies.

Gardenia jasminoides J. Ellis extract alleviated white matter damage through promoting the differentiation of oligodendrocyte precursor cells via suppressing neuroinflammation.

Increasing evidence has highlighted the role of white matter damage in the pathology of Alzheimer's disease (AD). Previous research has shown that a mixture of crocin analogues (GJ-4), Gardenia jasminoides J. Ellis extract, improved cognition in several AD mouse models, but the mechanism remains unclear. The aim of the present study was to investigate the effects and underlying mechanisms of GJ-4 on white matter damage. Proteomic analysis and western blotting results suggested that the level of myelin-related proteins, including myelin basic protein (MBP), myelin associated glycoprotein (MAG) and myelin associated oligodendrocyte basic protein (MOBP), was significantly decreased in the brain of PrP-hAßPPswe/PS1ΔE9 (APP/PS1) transgenic mice, and GJ-4 treatment increased the expressions of these proteins. This result revealed that GJ-4 could ameliorate myelin injury, suggesting that this might be a possible mechanism of GJ-4 on cognition. To validate the effects of GJ-4 on myelin, a metabolite of GJ-4, crocetin, which can pass through the blood-brain barrier, was applied in in vitro experiments. A mechanistic study revealed that crocetin significantly promoted the differentiation of primary cultured oligodendrocyte precursor cells to oligodendrocytes through up-regulation of nuclear Ki67 and transcription factor 2 (Olig2). Oligodendrocytes, the myelin-forming cells, have been reported to be lifelong partners of neurons. Therefore, to investigate the effects of crocetin on myelin and neurons, lysophosphatidylcholine (LPC)-treated primary mixed midbrain neuronal/glial culture was used. Immunofluorescence results indicated that crocetin treatment protected neurons and suppressed microglial activation against LPC-induced injury. To further discern the effects of GJ-4 on white matter injury and neuroinflammation, an LPC-induced mouse model was developed. GJ-4 administration increased oligodendrocyte proliferation, differentiation, and myelin repair. The mechanistic study indicated that GJ-4 improved white matter injury through the regulation of neuroinflammatory dysfunction. These data indicated that GJ-4 effectively repaired white matter damage in the LPC-treated mice. Thus, the present study supported GJ-4 as a potential therapeutic agent for AD and white matter related diseases.

Persistent myelin abnormalities in a third trimester-equivalent mouse model of fetal alcohol spectrum disorder.

BACKGROUND: Abnormal diffusion within white matter (WM) tracts has been linked to cognitive impairment in children with fetal alcohol spectrum disorder. Whether changes to myelin organization and structure underlie the observed abnormal diffusion patterns remains unknown. Using a third trimester-equivalent mouse model of alcohol exposure, we previously demonstrated acute loss of oligodendrocyte lineage cells with persistent loss of myelin basic protein and lower fractional anisotropy (FA) in the corpus callosum (CC). Here, we tested whether these WM deficits are accompanied by changes in: (i) axial diffusion (AD) and radial diffusion (RD), (ii) myelin ultrastructure, or (iii) structural components of the node of Ranvier. METHODS: Mouse pups were exposed to alcohol or air vapor for 4 h daily from postnatal day (P)3 to P15 (BEC: 160.4 ± 12.0 mg/dl; range = 128.2 to 185.6 mg/dl). Diffusion tensor imaging (DTI) and histological analyses were performed on brain tissue isolated at P50. Diffusion parameters were measured with Paravision™ 5.1 software (Bruker) following ex vivo scanning in a 7.0 T MRI. Nodes of Ranvier were identified using high-resolution confocal imaging of immunofluorescence for Nav 1.6 (nodes) and Caspr (paranodes) and measured using Imaris™ imaging software (Bitplane). Myelin ultrastructure was evaluated by calculating the G-ratio (axonal diameter/myelinated fiber diameter) on images acquired using transmission electron microscopy. RESULTS: Consistent with our previous study, high resolution DTI at P50 showed lower FA in the CC of alcohol-exposed mice (p = 0.0014). Here, we show that while AD (diffusion parallel to CC axons) was similar between treatment groups (p = 0.30), RD (diffusion perpendicular to CC axons) in alcohol-exposed subjects was significantly higher than in controls (p = 0.0087). In the posterior CC, where we identified the highest degree of abnormal diffusion, node of Ranvier length did not differ between treatment groups (p = 0.41); however, the G-ratio of myelinated axons was significantly higher in alcohol-exposed animals than controls (p = 0.023). CONCLUSIONS: High resolution DTI revealed higher RD at P50 in the CC of alcohol-exposed animals, suggesting less myelination of axons, particularly in the posterior regions. In agreement with these findings, ultrastructural analysis of myelinated axons in the posterior CC showed reduced myelin thickness in alcohol-exposed animals, evidenced by a higher G-ratio.

Life-long arsenic exposure damages the microstructure of the rat hippocampus.

Epidemiological studies demonstrate that arsenic exposure is associated with cognitive dysfunction. Experimental arsenic exposure models showed learning and memory deficits and molecular changes resembling the functional and pathologic neurodegeneration features. The present work focuses on hippocampal pathological changes in Wistar rats induced by continuous arsenic exposure from in utero up to 12 months of age, evaluated by magnetic resonance imaging along with immunohistochemistry. Diffusion-weighted images revealed age-related lower fractional anisotropy and higher radial-axial and mean diffusivity at 6 and 12 months, indicating that arsenic exposure leads to hippocampal demyelination. These structural alterations were paralleled by immunohistochemical changes that showed a significant loss of myelin basic protein in CA1 and CA3 regions accompanied by increased glial fibrillary acidic protein expression at all time-points studied. Concomitantly, arsenic exposure induced an altered morphology of astrocytes at all studied ages, whereas increased synaptogenesis was only observed at two months of age. These results suggest that environmental arsenic exposure is linked to impaired hippocampal connectivity and perhaps early glial senescence, which together might resemble a premature aging phenomenon leading to cognitive deficits.

Effect of metformin on 18F-fluorodeoxyglucose uptake and positron emission tomographic imaging.

Metformin is widely used to treat diabetes, but induces changes in glucose uptake in both normal organs and tumors. Here, we review the effects of metformin on the uptake of 18F-fludeoxyglucose (18F-FDG) in tissues and tumors, and its influence on 18F-FDG positron emission tomographic imaging (18F-FDG PET), as well as the mechanisms involved. This is an important issue, because metformin has diverse effects on tissue uptake of 18F-FDG, and this can affect the quality and interpretation of PET images. Metformin increases glucose uptake in the gastrointestinal tract, cerebral white matter, and the kidney, while regions of the cerebrum associated with memory show decreased glucose uptake, and the myocardium shows no change. Hepatocellular carcinoma and breast cancer show increased glucose uptake after metformin administration, while thyroid cancer shows decreased uptake, and colon and pancreatic cancers show no change. A high-energy diet increases 18F-FDG uptake, but this effect is blocked by metformin. Withdrawal of metformin 48 h before PET image acquisition is widely recommended. However, based on our review of the literature, we propose that the differentiation of metformin discontinuation could be reasonable. But future clinical trials are still needed to support our viewpoint.

Ferrostatin-1 Alleviates White Matter Injury Via Decreasing Ferroptosis Following Spinal Cord Injury.

Spinal cord injury (SCI), a devastating neurological impairment, usually imposes a long-term psychological stress and high socioeconomic burden for the sufferers and their family. Recent researchers have paid arousing attention to white matter injury and the underlying mechanism following SCI. Ferroptosis has been revealed to be associated with diverse diseases including stroke, cancer, and kidney degeneration. Ferrostatin-1, a potent inhibitor of ferroptosis, has been illustrated to curb ferroptosis in neurons, subsequently improving functional recovery after traumatic brain injury (TBI) and SCI. However, the role of ferroptosis in white matter injury and the therapeutic effect of ferrostatin-1 on SCI are still unknown. Here, our results indicated that ferroptosis played a pivotal role in the secondary white matter injury, and ferrostatin-1 could reduce iron and reactive oxygen species (ROS) accumulation and downregulate the ferroptosis-related genes and its products of IREB2 and PTGS2 to further inhibit ferroptosis in oligodendrocyte, finally reducing white matter injury and promoting functional recovery following SCI in rats. Meanwhile, the results demonstrated that ferrostatin-1 held the potential of inhibiting the activation of reactive astrocyte and microglia. Mechanically, the present study deciphers the potential mechanism of white matter damage, which enlarges the therapeutic effects of ferrostatin-1 on SCI and even in other central nervous system (CNS) diseases existing ferroptosis.

Selective activation of cannabinoid receptor-2 reduces white matter injury via PERK signaling in a rat model of traumatic brain injury.

BACKGROUND AND PURPOSE: Traumatic brain injury (TBI) destroys white matter, and this destruction is aggravated by secondary neuroinflammatory reactions. Although white matter injury (WMI) is strongly correlated with poor neurological function, understanding of white matter integrity maintenance is limited, and no available therapies can effectively protect white matter. One candidate approach that may fulfill this goal is cannabinoid receptor 2 (CB2) agonist treatment. Here, we confirmed that a selective CB2 agonist, JWH133, protected white matter after TBI. METHODS: The motor evoked potentials (MEPs), open field test, and Morris water maze test were used to assess neurobehavioral outcomes. Brain tissue loss, WM damage, Endoplasmic reticulum stress (ER stress), microglia responses were evaluated after TBI. The functional integrity of WM was measured by diffusion tensor imaging (DTI) and transmission electron microscopy (TEM). Primary microglia and oligodendrocyte cocultures were used for additional mechanistic studies. RESULTS: JWH133 increased myelin basic protein (MBP) and neurofilament heavy chain (NF200) levels and anatomic preservation of myelinated axons revealed by DTI and TEM. JWH133 also increased the numbers of oligodendrocyte precursor cells and mature oligodendrocytes. Furthermore, JWH133 drove microglial polarization toward the protective M2 phenotype and modulated the redistribution of microglia in the striatum. Further investigation of the underlying mechanism revealed that JWH133 downregulated phosphorylation of the protein kinase R (PKR)-like endoplasmic reticulum (ER) kinase (PERK) signaling pathway and its downstream signals eukaryotic translation initiation factor 2 α (eIF2α), activating transcription factor 4 (ATF4) and Growth arrest and DNA damage-inducible protein (GADD34); this downregulation was followed by p-Protein kinase B(p-Akt) upregulation. In primary cocultures of microglia and oligodendrocytes, JWH133 decreased phosphorylated PERK expression in microglia stimulated with tunicamycin and facilitated oligodendrocyte survival. These data reveal that JWH133 ultimately alleviates WMI and improves neurological behavior following TBI. However, these effects were prevented by SR144528, a selective CB2 antagonist. CONCLUSIONS: This work illustrates the PERK-mediated interaction between microglia and oligodendrocytes. In addition, the results are consistent with recent findings that microglial polarization switching accelerates WMI, highlighting a previously unexplored role for CB2 agonists. Thus, CB2 agonists are potential therapeutic agents for TBI and other neurological conditions involving white matter destruction.

Triptolide protects against white matter injury induced by chronic cerebral hypoperfusion in mice.

White matter injury is the major pathological alteration of subcortical ischemic vascular dementia (SIVD) caused by chronic cerebral hypoperfusion. It is characterized by progressive demyelination, apoptosis of oligodendrocytes and microglial activation, which leads to impairment of cognitive function. Triptolide exhibits a variety of pharmacological activities including anti-inflammation, immunosuppression and antitumor, etc. In this study, we investigated the effects of triptolide on white matter injury and cognitive impairments in mice with chronic cerebral hypoperfusion induced by the right unilateral common carotid artery occlusion (rUCCAO). We showed that triptolide administration alleviated the demyelination, axonal injury, and oligodendrocyte loss in the mice. Triptolide also improved cognitive function in novel object recognition test and Morris water maze test. In primary oligodendrocytes following oxygen-glucose deprivation (OGD), application of triptolide (0.001-0.1 nM) exerted concentration-dependent protection. We revealed that the protective effect of triptolide resulted from its inhibition of oligodendrocyte apoptosis via increasing the phosphorylation of the Src/Akt/GSK3ß pathway. Moreover, triptolide suppressed microglial activation and proinflammatory cytokines expression after chronic cerebral hypoperfusion in mice and in BV2 microglial cells following OGD, which also contributing to its alleviation of white matter injury. Importantly, mice received triptolide at the dose of 20 µg·kg-1·d-1 did not show hepatotoxicity and nephrotoxicity even after chronic treatment. Thus, our results highlight that triptolide alleviates whiter matter injury induced by chronic cerebral hypoperfusion through direct protection against oligodendrocyte apoptosis and indirect protection by inhibition of microglial inflammation. Triptolide may have novel indication in clinic such as the treatment of chronic cerebral hypoperfusion-induced SIVD.

Air Pollution Particulate Matter Amplifies White Matter Vascular Pathology and Demyelination Caused by Hypoperfusion.

Cerebrovascular pathologies are commonly associated with dementia. Because air pollution increases arterial disease in humans and rodent models, we hypothesized that air pollution would also contribute to brain vascular dysfunction. We examined the effects of exposing mice to nanoparticulate matter (nPM; aerodynamic diameter ≤200 nm) from urban traffic and interactions with cerebral hypoperfusion. C57BL/6 mice were exposed to filtered air or nPM with and without bilateral carotid artery stenosis (BCAS) and analyzed by multiparametric MRI and histochemistry. Exposure to nPM alone did not alter regional cerebral blood flow (CBF) or blood brain barrier (BBB) integrity. However, nPM worsened the white matter hypoperfusion (decreased CBF on DSC-MRI) and exacerbated the BBB permeability (extravascular IgG deposits) resulting from BCAS. White matter MRI diffusion metrics were abnormal in mice subjected to cerebral hypoperfusion and worsened by combined nPM+BCAS. Axonal density was reduced equally in the BCAS cohorts regardless of nPM status, whereas nPM exposure caused demyelination in the white matter with or without cerebral hypoperfusion. In summary, air pollution nPM exacerbates cerebrovascular pathology and demyelination in the setting of cerebral hypoperfusion, suggesting that air pollution exposure can augment underlying cerebrovascular contributions to cognitive loss and dementia in susceptible elderly populations.