Objective This study combined static and dynamic amplitude of low-frequency fluctuation (sALFF and dALFF) to investigate the abnormalities of local spontaneous brain activity in patients with chronic tinnitus and their relationships with the spatial distributions of multiple neurotransmitters, thereby providing a theoretical basis for understanding the neural mechanisms underlying chronic tinnitus. Methods This study included 80 patients with chronic tinnitus and 68 healthy controls. Resting-state functional magnetic resonance imaging (rs-fMRI) data were used to calculate sALFF and dALFF metrics in both groups, and between-group differences were subsequently compared. Furthermore, the relationships between ALFF alterations and neurotransmitter distributions in patients with chronic tinnitus were analyzed. Results Compared with the healthy control group, the sALFF value in the left superior temporal gyrus of patients with chronic tinnitus was significantly increased, and the dALFF value in the right precuneus was significantly decreased (GRF correction, voxel level P<0.001, cluster level P<0.05). Moreover, the alterations of sALFF correlated with the spatial distribution of serotonin transporter, dopamine, glutamate systems, and GABAergic, and the alterations of dALFF correlated with the spatial distribution of serotonin transporter, dopaminergic, and the vesicular acetylcholine transporter (VAChT). Conclusions Chronic tinnitus exhibits not only abnormalities in sALFF, but also aberrant dynamic temporal fluctuations, which spatially correlate with the distribution patterns of different neurotransmitter systems, thereby deepening the understanding of the neural mechanisms underlying chronic tinnitus.
Objective Our study aimed to investigate cortical thickness (CT) alterations in Parkinson’s disease (PD) patients with and without diabetes mellitus (DM), and explore the correlation between DM, CT, and cognitive function. Methods A total of 135 participants were enrolled, including 16 PD patients with DM (PD-DM), 87 PD patients without DM (PD-nonDM), and 32 healthy controls (NC). All participants underwent 3.0T MRI, and CT was analyzed using Computational Anatomy Toolbox (CAT). Clinical data and blood parameters were also collected. Group differences were assessed with covariate-adjusted t-tests, and correlations between DM, CT, and Mini-Mental State Examination (MMSE) scores were analyzed using partial Spearman correlation and multiple regression. Results No significant clinical differences between PD-DM and PD-nonDM were observed. Compared with NC, PD-nonDM showed cortical thinning in the left orbitofrontal cortex, and PD-DM group exhibited reduced CT in the right parahippocampal and entorhinal regions, after adjusting for confounding factors. Compared with PD-nonDM, PD-DM patients revealed significant cortical thinning in bilateral entorhinal cortex. DM status was correlated with bilateral entorhinal CT (left: partial r=-0.227, p=0.022; right: partial r=-0.209, p=0.036), but not MMSE, after controlling for age and sex ratio. MMSE scores positively correlated with CT in the left inferior parietal and right parahippocampal gyrus (FWE corrected, k > 100 voxels). Interpretation DM is associated with cortical thinning in cognitive-related regions (especially the entorhinal cortex) in PD, potentially before significant cognitive decline captured by MMSE. These findings provide insights into PD with DM mechanisms.
Diethyl phthalate (DEP) is a ubiquitous low-molecular-weight phthalate, yet its influence on Alzheimer’s disease (AD) progression remains unclear. We combined network toxicology and molecular docking with in vivo validation to determine whether subchronic DEP exposure aggravates AD-like pathology and to define the involvement of PI3K/Akt signaling. Bioinformatic analysis identified 133 shared targets between phthalate-related proteins and AD-associated genes, highlighted PI3K/Akt signaling, and nominated PIK3CA as a potential DEP-binding target. Seven-month-old male 5XFAD and wild-type mice received DEP (3,000mgkg−1 day−1 by oral gavage) for 54 days as a proof-of-principle high-dose exposure paradigm; a rescue cohort received the Akt activator SC79 (2mgkg−1 day−1 intraperitoneally for 7 days). DEP impaired spatial learning and memory without altering gross locomotor activity, increased hippocampal and cortical amyloid plaques and A11-reactive oligomers, reduced synaptic proteins, and was associated with greater hippocampal neuronal injury in 5XFAD mice. These changes were accompanied by reduced AKT and GSK3β phosphorylation, increased BACE1, altered proteostasis-associated markers, and enhanced apoptotic signaling. Pharmacological Akt activation partially restored cognitive performance, reduced amyloid burden, preserved synaptic and neuronal integrity, and partially attenuated the associated molecular alterations. Together, these findings indicate that DEP aggravates AD-like phenotypes in an amyloid-vulnerable brain, implicate Akt-centered signaling as a functionally relevant pathway, and nominate PIK3CA as a candidate molecular target linking phthalate exposure to amyloid-associated neurodegeneration.
Ischemic stroke (IS) remains a devastating cerebrovascular disease associated with high morbidity, mortality, and disability, while effective restorative therapies remain limited, highlighting an urgent unmet clinical need. Post-stroke angiogenesis contributes to vascular remodeling, restoration of cerebral blood flow, and neurovascular regeneration, making it a promising therapeutic target for IS repair. Salvianolic acid A (SAA), a phenolic acid from Salvia miltiorrhiza (Danshen), protects vascular endothelial cells and enhances neurogenesis, but its role and mechanisms in post-stroke angiogenesis remain unclear. This study investigated the effects and molecular mechanisms of SAA on post-stroke angiogenesis in vitro and in vivo. In vivo, an autologous thrombus-induced rat stroke model was established by electrocoagulation to evaluate the effects of SAA on neurological recovery and angiogenesis. In vitro, hydrogen peroxide (H₂O₂)-induced oxidative damage in human brain microvascular endothelial cells (HBMECs) was used to investigate the protective effects of SAA on endothelial function. Network pharmacology, molecular docking, and surface plasmon resonance (SPR) identified targets, with mechanistic verification both in vitro and in vivo. In the rat stroke model, SAA improved neurological deficits and enhanced functional recovery in a dose- and time-dependent manner. It also increased peri-infarct microvessel density, promoted vascular maturation, and upregulated pro-angiogenic factors (VEGF-A, Ang-1) and tight junction proteins (TJPs) (ZO-1, Occludin, Claudin-5). In HBMECs, SAA alleviated oxidative stress, enhanced proliferation, migration, and tube formation. Network pharmacology and SPR confirmed AKT as a core target of SAA, further activating the Nrf2 signaling pathway. AKT inhibitor MK-2206 counteracted the pro-angiogenic effect of SAA. In conclusion, SAA promotes post-stroke angiogenesis by targeting AKT and activating Nrf2-mediated antioxidant signaling, thereby protecting vascular endothelial function and improving neurological recovery. These findings provide new insights into vascular repair after IS and highlight SAA as a potential therapeutic candidate for stroke recovery via modulating angiogenesis.
The beneficial effects of aerobic exercise in aging are well established but can be limited by low aerobic capacity. Resistance exercise is also beneficial, yet little is known about how intrinsic aerobic capacity influences resistance exercise performance or related motor outcomes in advanced age. We trained 18–24-month-old rats selectively bred for low (LCR) or high (HCR) aerobic capacity to perform a unilateral forelimb resistance exercise task and assessed task engagement, force production, and response duration. Orolingual motor function was evaluated as a complementary measure of cranial motor performance. Circulating extracellular vesicles (EVs) were measured as potential systemic correlates of intrinsic aerobic capacity and resistance exercise. Task acquisition was similar between LCR and HCR rats as was task engagement across increasing force requirements. HCR rats produced greater force relative to body weight at lower force requirements, whereas LCR rats exhibited longer press–hold durations across all requirements. Licking speed and total licks were greater in HCR rats, while tongue motility declined over time in sedentary LCR rats but increased in resistance exercise-trained LCR rats. Circulating EV numbers differed between LCR and HCR groups but not as a function of exercise. Together, these findings indicate that low intrinsic aerobic capacity does not affect resistance exercise engagement and performance in aging and that resistance exercise may confer functional benefits beyond the trained musculature. Resistance exercise may therefore represent a viable alternative for preserving muscle function during aging in individuals with limited aerobic capacity.
BACKGROUND:Small cell lung cancer (SCLC) exhibits the highest incidence of brain metastasis among lung cancer subtypes, often leading to severe neurological dysfunction and poor prognosis. However, preclinical orthotopic brain parenchymal SCLC xenograft models that recapitulate relevant neurotoxic injuries are still scarce. This study aimed to establish a SCLC brain parenchymal model using stereotaxic-guided intracranial injection in BALB/c-nu and systematically characterize the resulting neurological injury. METHODS:Mice in model group received an intracranial injection of 1 × 106 SCLC-1 cells in 5 μL PBS. Neurobehavioral evaluations including the open field test and Morris water maze (MWM) were performed at days 14 and 21 post-injection. Following behavioral assessment, all mice were euthanized, brain tissues were harvested for hematoxylin and eosin (HE) staining. Immunofluorescence (IF) staining was utilized to detect synaptic markers, Synaptophysin/PSD95, neuroinflammation/neuron markers, CK19/Iba-1/NeuN, as well as tight junction proteins, Occludin, ZO1. Immunohistochemistry (IHC) was applied to examine CD56 and Chromogranin A expression. RESULTS:Distinct tumor foci developed at the intracranial injection site in model mice, accompanied by robust inflammatory cell infiltration. IHC revealed strong CD56 and Chromogranin A expression within tumor lesions, confirming the neuroendocrine characteristics of intracranial SCLC lesions. Neurobehavioral assays uncovered evident neurological dysfunction in tumor-bearing animals. Specifically, model mice exhibited significantly prolonged escape latency in the MWM, indicative of defective spatial learning and memory capacity. Meanwhile, shorter total movement distance and longer immobility time were shown in the model group in the open field test, which reflects reduced spontaneous activity. IF further demonstrated multiple pathological alterations: decreased expression and fragmented distribution of tight junction proteins Occludin and ZO-1; a prominent decline in the colocalization coefficient of Synaptophysin and PSD-95, suggestive of synaptic structural disruption, massive accumulation of Iba-1-labeled microglia surrounding CK19-positive tumor lesions; and a pronounced loss of NeuN-expressing mature neurons. CONCLUSIONS:Stereotaxic-guided intraparenchymal injection can be used to establish a stable intracranial orthotopic implantation model of SCLC in BALB/c-nu nude mice. This model can mimic partial typical pathological changes of clinical SCLC brain metastasis, and pathological features including tumor lesions accompanied by inflammatory infiltration, synaptic structural damage, microglial activation and neuronal loss can be observed in the model. Among existing relevant studies, reports on constructing intracranial lesion models of SCLC via intracranial injection remain scarce. However, this model has certain limitations and cannot fully reproduce the complete pathological process of clinical brain metastasis triggered by spontaneous tumor migration and hematogenous dissemination.
Sensorimotor incongruence can induce abnormal limb perceptions such as heaviness, yet effective interventions remain scarce. This study examined whether transcutaneous electrical nerve stimulation (TENS) modulates heaviness induced by sensorimotor incongruence in healthy participants. Seventy-one healthy adults were randomly assigned to a control group (electrodes only), a low-frequency group (4 Hz, 100 μs), a high-frequency group (100 Hz, 100 μs), or a high-pulse-width group (100 Hz, 200 μs). Sensorimotor incongruence was induced via a 250 ms visuomotor delay paradigm. Changes in perceived heaviness were assessed by visual analogue scale and analysed using multiple regression and Bayesian regression with region of practical equivalence (ROPE). Neither stimulation group, psychological components, nor stimulation preference significantly predicted heaviness change (adjusted R² = -0.03, F = 0.55, p = .74); ROPE analysis was indeterminate for all Bayesian coefficients. Model-based clustering revealed that a subset of participants exhibited large perceptual changes, suggesting that future research should identify factors that discriminate responders from non-responders. These findings indicate that TENS does not modulate sensorimotor incongruence-induced heaviness, and highlight that reliable induction of this perception is a prerequisite for intervention research. Paradigm standardization and identification of susceptibility factors warrant future investigation.
Objective To explore glymphatic function and white matter microstructural alterations in high-frequency episodic migraine (HFEM). Methods This study included 31 healthy controls (HCs), 44 patients with low-frequency episodic migraine (LFEM), and 27 with HFEM. Glymphatic function was indirectly assessed using diffusion tensor image analysis along the perivascular space (DTI-ALPS), while white matter integrity was examined using tract-based spatial statistics (TBSS). Results The ALPS index was higher in LFEM than HFEM. In the combined migraine cohort, it was negatively associated with attack frequency, showed a trend toward a negative association with the Migraine Disability Assessment Scale (MIDAS) score, and was positively associated with the visual analogue scale (VAS) score. Exploratory mediation analysis indicated that attack frequency showed a significant statistical mediating role in the association between the ALPS index and MIDAS score. No significant between-group differences in white matter FA survived correction for multiple comparisons in the TBSS analysis. Conclusions The ALPS index showed a frequency-related pattern, with relatively higher values in LFEM and lower values in HFEM, suggesting differences in glymphatic function across attack-frequency stages of episodic migraine. Attack frequency showed a significant statistical mediating role in the association between glymphatic function and migraine-related disability. The exploratory TBSS analysis did not identify significant white matter FA differences after correction for multiple comparisons.
Parkinson's disease (PD) is a complex neurodegenerative disorder in which environmental toxins play a critical etiological role. Rotenone, a classical mitochondrial complex I inhibitor used to model PD, exerts its neurotoxicity through incompletely defined downstream molecular networks. Here, we integrated multiple PD transcriptomic datasets from GEO with predicted rotenone targets, applied machine learning to screen core candidate genes, and analyzed their cellular localization using single-cell transcriptomics. Molecular docking was performed to assess target-rotenone binding, and functional validation was carried out in primary dopaminergic neurons via lentivirus-mediated gene manipulation, Western blotting, qRT-PCR, and mitochondrial function assays. This approach identified and validated a six-gene core network (AKR1C2, AKR1C3, CES1, CTSS, DRD2, HSPA1A), several of which were predicted to directly bind rotenone. Single-cell analysis confirmed their enrichment in PD dopaminergic neurons, and immunofluorescence validated their co-localization with the dopaminergic marker TH. In rotenone-treated neurons, all six genes except DRD2, as well as KRT8, were significantly upregulated at both the mRNA and protein levels; rotenone also impaired mitochondrial Complex I activity and ATP production, and increased α-synuclein expression. In silico knockout revealed that AKR1C2-perturbed genes were enriched in keratinization pathways. Functional experiments demonstrated that AKR1C2 positively regulates KRT8. Notably, AKR1C2 knockdown not only reduced KRT8 levels but also rescued mitochondrial function, neuronal viability, and rotenone-impaired action potential firing, whereas AKR1C2 overexpression exacerbated these deficits. Critically, KRT8 re‑expression reversed the protective effects of AKR1C2 knockdown, while KRT8 knockdown reversed AKR1C2 overexpression‑induced impairments, collectively confirming the causal role of the AKR1C2-KRT8 axis. Collectively, these findings delineate a multi-node molecular network downstream of rotenone and provide the first experimental validation of a novel AKR1C2-KRT8 regulatory axis in dopaminergic neuron injury.
BACKGROUND:Cerebral palsy (CP) is characterized by persistent motor impairment and may be accompanied by sustained neuroinflammation. Metabolic reprogramming is increasingly recognized as an important regulator of microglial inflammatory responses; however, its involvement in the effects of Tuina remains unclear. OBJECTIVE:To evaluate the effects of Tuina in a neonatal hypoxic-ischemic mouse model of CP and determine whether its effects are accompanied by changes in cortical energy metabolism and microglial inflammatory profiles. METHODS:Mice were assigned to Sham, CP, and CP+Tuina groups. Tuina was administered for 15 min/day, 6 days/week, for 7 weeks. Growth, neurobehavioral performance, and brain histopathology were assessed. Cortical protein lactylation profiles, glycolytic activity, mitochondrial respiration, metabolic enzyme activities, and ATP content were evaluated. Microglia-associated metabolic alterations were examined by double immunofluorescence staining of Iba1 with GLUT1 or COX IV. Activation-associated markers and inflammatory cytokines were also measured. In vitro, BV2 microglial cells were treated with oxamate or rotenone to modulate glycolysis and mitochondrial respiration, respectively. RESULTS:Tuina improved body-weight gain, motor coordination, cognitive performance, and histopathological changes in CP mice. Protein lactylation profiling identified alterations in pathways related to glycolysis, the tricarboxylic acid cycle, and oxidative phosphorylation. CP mice exhibited increased cortical glycolytic activity and impaired mitochondrial respiration, which were partially attenuated by Tuina. In Iba1-positive microglia, CP was associated with increased GLUT1 and decreased COX IV expression, whereas Tuina partially reversed these changes. Tuina also reduced CD86 and iNOS expression and the levels of TNF-α and IL-1β, while further increasing CD206, Arg1, IL-10, and IL-4. In BV2 cells, glycolysis inhibition reduced pro-inflammatory-associated responses, whereas mitochondrial inhibition induced glycolytic compensation and enhanced pro-inflammatory-associated markers and cytokines. CONCLUSION:Tuina was associated with improved neurobehavioral outcomes, partial restoration of cortical metabolic homeostasis, and modulation of microglial inflammatory profiles in CP mice. The findings support a close relationship between metabolic reprogramming and microglia-mediated inflammation, although the causal role of these metabolic changes in the in vivo effects of Tuina requires further investigation.
Treatment for pediatric acute lymphoblastic leukemia (ALL) is associated with neurotoxicity and leads to chemotherapy-related cognitive impairment (CRCI) in 40–70% of survivors. Methotrexate (MTX), a key component of ALL chemotherapy regimens, is a major contributor to CRCI. However, because ALL chemotherapy involves multiple agents, the independent contribution of MTX to the previously observed metabolic changes remains unclear.Using a juvenile rat model (N=40, evenly split between males and females) designed to isolate MTX-specific effects within a pediatric-relevant context, we administered six intraperitoneal (0.5mg/kg per dose) and four intrathecal (1mg/kg per dose) MTX injections and performed CSF metabolomics at the time of the first intrathecal injection and last. Five weeks later, we assessed spatial and visual memory using object placement (OP) and novel object recognition (OR) behavioral tests.MTX-treated rats exhibited spatial and visual memory impairments compared with controls. In accordance with our previous results and MTX’s mechanism of action, determinants of one-carbon metabolism were downregulated in the CSF of MTX-treated animals between the timepoints tested. In contrast, transsulfuration pathway metabolites such as cystathionine and cysteine were upregulated. Last, MTX treatment also induced alterations in lipid metabolism, with a significant over-representation of 8 plasmalogens and 9 phosphatidylcholines.These findings support the use of CSF metabolomics to characterize MTX-associated neurotoxicity and provide insight into metabolic pathways that may be associated with CRCI and therefore warrant future mechanistic investigation.
INTRODUCTION:Alzheimer's disease (AD) is characterized by progressive cognitive decline and brain network dysfunction. EEG microstates offer a sight into rapid network dynamics. However, microstate alterations in AD during waking and different sleep stages remain unexplored. METHODS:Overnight EEG was recorded from 15 AD patients and 15 healthy controls. Sleep stages (Wake, N1, N2, N3, REM) were manually scored. Microstate analysis extracted temporal parameters and transition probabilities separately for each sleep stage using a common set of grand-mean template maps derived from all stages. Linear mixed models assessed group differences, and correlations examined associations with MMSE. RESULTS:AD patients showed significantly longer durations compared to HC (Group main effect: F(1,28) = 6.78, p_FDR = 0.042) in mean duration of class A, with the largest difference during wakefulness (p = 0.018, q = 0.046). Mean occurrence of class D was significantly lower in AD (F(1,28) = 5.44, p_FDR = 0.049), with significant reductions during wakefulness and N1. Mean Occurrence of class C showed both a significant Group main effect (F(1,28) = 5.28, p_FDR = 0.049) and a Group × Sleep Stage interaction (F(4112) = 3.31, p_FDR = 0.047) were observed, with AD patients showing lower occurrence during wakefulness and N1. For transition probabilities, AD patients showed significantly increased corrected Class B→A transition (DeltaTM_B→A), but reduced corrected Class D→B transition (DeltaTM_D→B) and raw Class C→D transition (OrgTM_C→D) (all p_FDR < 0.05). Critically, the Group × Sleep Stage interaction for the corrected Class A→D transition (DeltaTM_A→D) reached significance (F(4112) = 6.12, p_FDR = 0.015), with the group difference largest during wakefulness (p = 0.004, q = 0.029). Partial correlations revealed that corrected B→A transition probability negatively correlated with MMSE (r = -0.642, p < 0.001); MeanOccurrence_C (r = 0.487, p = 0.003) and MeanOccurrence_D (r = 0.532, p = 0.001) also showed significant correlations with MMSE. CONCLUSIONS:This is the first study to report that AD patients exhibit altered microstate parameters and transition probabilities across sleep stages. Present findings suggest that sleep-stage-resolved microstate analysis may offer a new tool for assessing AD.
Introduction： Mild cognitive impairment (MCI) related to cerebral small vessel disease (CSVD) is a key window for intervention, but its pathogenesis has not yet been elucidated. This study investigated the alterations in cortical morphological similarity network (MSN), choroid plexus (ChP) volume, and glycolipid levels in CSVD patients with MCI, and their associations with cognitive impairment. Methods： The MRI data, glycolipid level values, and neuropsychological scores from 33 CSVD patients with MCI (CSVD-MCI), 33 CSVD patients with cognitive normal (CSVD-CN) and 33 normal controls (NC) were collected. Additionally, 10 CSVD-MCI patients and 10 CSVD-CN patients underwent MRI scanning and neuropsychological assessment again after an average interval of 1.3 years. Next, between-group comparisons, longitudinal comparisons, correlation analysis, and neuroimaging transcriptome correlation analysis based on the Allen Human Brain Atlas database were conducted. Results： (1) In the CSVD-MCI group, the MSN topological properties, MSN gradient scores, bilateral ChP volumes, high-density lipoprotein cholesterol value, and blood glucose value were significantly abnormal at baseline and follow-up. (2) The change in MSN gradient 2 score was associated with 444 genes and biological pathways such as synaptic transmission and glucose metabolism. (3) Blood glucose levels and specific high-order network gradient 2 scores were significantly correlated with cognitive performance. (4) The association between increased ChP volume and decreased global cognitive scores was mediated by the abnormal gradient 2 scores of the limbic network. Conclusion： CSVD-related MCI was closely associated with increased ChP volume and MSN disruption.
Reperfusion therapies following stroke can contribute to further brain injury.Inhibition of G9a has been demonstrated to increase BDNF expression, thereby exerting neuroprotective effects. Isoquercetin (ISO) has shown neuroprotective potential, but its molecular mechanisms are not fully known. This study aimed to investigate the role and mechanism of ISO in improving cerebral ischemia-reperfusion injury, in relation to G9a/H3K9me2/BDNF pathway. A rat middle cerebral artery occlusion (MCAO) model and an oxygen-glucose deprivation/reoxygenation (OGD/R) neuronal model were used. Neurological scores, infarct volume, brain water content, neuronal morphology, apoptosis and cell viability were evaluated. Moreover, a G9a overexpression plasmid was constructed to verify mechanism specificity. G9a and H3K9me2 expression levels were assessed by RT-PCR and western blotting. BDNF levels were measured by ELISA, oxidative stress by ROS assays and H3K9me2 enrichment at the BDNF promoter by chromatin immunoprecipitation. Cerebral I/R injury significantly increased G9a and H3K9me2 expression, leading to reduced BDNF levels and enhanced neuronal apoptosis. ISO treatment decreased G9a/H3K9me2 expression, increased BDNF levels, improved neurological function and reduced neuronal damage both in vivo and in vitro. G9a overexpression reversed these protective effects. Isoquercetin alleviates cerebral I/R injury by inhibiting G9a-mediated histone methylation and promoting BDNF expression, highlighting a novel epigenetic mechanism for stroke therapy
BACKGROUND:Cerebral microbleeds (CMBs), a marker of cerebral small vessel disease and common in older adults, are associated with cognitive impairment. However, the neurovascular mechanisms remain incompletely understood. We investigated whether cerebral blood flow (CBF) abnormalities and CBF network changes were associated with cognitive impairment in patients with CMBs. METHODS:In this cross-sectional study, 111 participants with CMBs and 148 controls underwent neuropsychological assessment and arterial spin labeling MRI. Following propensity score matching, CBF and CBF network analyses were performed in 76 matched CMB-control pairs. Whole-brain and regional CBF were assessed, and individual CBF networks were constructed from temporal correlations among regional CBF signals. RESULTS:Participants with CMBs exhibited poorer performance in memory, language, and executive functions. Imaging analyses revealed a heterogeneous perfusion pattern in the CMB group, with relatively increased perfusion in lateral cortical regions and reduced perfusion in medial and deep brain structures. Higher temporal CBF was associated with lower cognitive scores, whereas lower caudate CBF was associated with reduced language and executive performance. Patients with CMBs also showed reduced nodal efficiency in temporal regions, including the superior temporal pole. Mediation analysis identified significant indirect associations between higher temporal CBF and lower MMSE scores through right superior temporal pole nodal efficiency. CONCLUSIONS:Cognitive impairment in patients with CMBs was associated with heterogeneous CBF abnormalities and disrupted CBF network organization. These findings suggest that perfusion abnormalities may provide clinically relevant insight into the neurovascular basis of CMB-related cognitive impairment.
Subarachnoid hemorrhage (SAH) is a devastating cerebrovascular disease that causes severe early brain injury (EBI), in which neuronal apoptosis and oxidative stress are major contributors to neurological dysfunction. However, the molecular mechanisms underlying EBI remain incompletely understood. Transcriptomic analyses of the GSE73378 and GSE36791 datasets identified solute carrier family 22 member 4 (SLC22A4) as a SAH-associated gene. Public single-cell RNA sequencing data further revealed that SLC22A4 was predominantly enriched in astrocytes following SAH. In a mouse SAH model, neuronal loss, apoptosis, and reactive oxygen species (ROS) production were significantly increased and accompanied by elevated SLC22A4 expression. AAV-mediated SLC22A4 overexpression alleviated neuronal injury, reduced apoptosis and oxidative stress, and restored the expression of apoptosis- and stress-related proteins in vivo. Mechanistically, co-expression and enrichment analyses identified myeloid cell leukemia-1 (MCL1) as a candidate gene associated with SLC22A4. Their positive correlation was validated in independent transcriptomic cohorts and experimental models. In OxyHb-treated astrocytes, SLC22A4 overexpression increased MCL1 expression and attenuated apoptosis- and oxidative stress-related responses, whereas pharmacological inhibition of MCL1 with S63845 partially reversed these protective effects. Collectively, these findings suggest that SLC22A4 alleviates EBI after SAH, partly through MCL1-associated suppression of apoptosis and oxidative stress.
OBJECTIVE:To investigate neurovascular coupling (NVC) alterations in pediatric acute lymphoblastic leukemia (ALL) patients following chemotherapy using multimodal neuroimaging. METHODS:We combined arterial spin labeling (ASL) and resting-state functional MRI (rs-fMRI) to assess the relationship between cerebral blood flow (CBF) and blood oxygenation level-dependent (BOLD)-derived resting-state metrics, including amplitude of low-frequency fluctuations (ALFF), fractional amplitude of low-frequency fluctuations (fALFF), regional homogeneity (ReHo), and degree centrality (DC), in 23 children with ALL (age range, 7-15 years) and 30 healthy controls (age range, 6-13 years). RESULTS:Children with ALL assessed after chemotherapy showed significant regional differences in NVC indices compared with healthy controls. The ALL group demonstrated significantly lower Perceptual Reasoning Index (PRI) and Full-Scale Intelligence Quotient (FSIQ) scores after adjustment for education (p < 0.05). No significant between-group differences were found in the whole-brain CBF-ALFF, CBF-fALFF, CBF-ReHo, or CBF-DC coefficients (all p > 0.05). Regional NVC analysis revealed consistently reduced ratios in the right middle temporal gyrus and increased ratios in several left-sided cortical and subcortical regions, including the hippocampus, thalamus, and lingual gyrus. After false discovery rate (FDR) correction, no significant correlations were found between regional NVC metrics and cognitive scores (all corrected q > 0.05). CONCLUSION:Children with ALL show altered NVC in multiple brain regions after chemotherapy. However, no direct associations with cognitive scores survived stringent correction, and these findings should be considered preliminary imaging evidence of regional brain functional differences in this population.
Ischemic stroke is caused by obstruction of a blood vessel reducing blood supply to a specific brain region and is one of the leading causes of disability worldwide. The pathophysiology of ischemic brain damage involves the formation of glial scars that can further limit functional recovery. Inhibitory chondroitin sulfate proteoglycans (CSPGs) are the major components of glial scars, but there is little information regarding their expression and distribution in either the damaged brain or, secondarily, in the more distant cervical spinal cord region after the chronic ischemic stroke. Here, we used a preclinical photothrombotic model to induce ischemic stroke and immunohistochemistry to characterize the expression of various CSPGs and neuroinflammatory cells that may produce CSPGs in (1) the peri-infarct area, a potentially salvageable area surrounding the ischemic core, and (2) the white (corticospinal tract) and gray matter regions of the cervical spinal cord. Our results demonstrate upregulation of neuroinflammatory cells and CSPG molecules in the damaged brain and cervical spinal cord at two months post-stroke. Reductions in aggrecan + perineuronal nets (PNNs) and increases in Wisteria floribunda agglutinin (WFA) + PNNs were identified in the lesional cortex. In the spinal cord, aggrecan levels were similar, but there was increased WFA + intensity. In addition, reactive astrocytes and microglia were increased and colocalized with CSPGs, which are responsible for the generation of CSPGs to persistent chronic neuroinflammation post-ischemia stroke.
Background Alzheimer's disease (AD) is a neurodegenerative disorder with a global prevalence, currently lacking effective treatments and posing a major public health challenge due to the burden it places on healthcare systems while affecting millions of people. Melatonin is a hormone with considerable potential for treating various neurodegenerative disorders, including AD. The mechanisms responsible for melatonin's therapeutic benefits in Alzheimer's disease (AD) require further elucidation. This study was designed to investigate the mechanisms by which melatonin exerts its effects in APP/PS1 mice. Methods The Morris water maze was used to assess the performance of melatonin-treated APP/PS1 mice. Haematoxylin&Eosin and Nissl staining were conducted to observe the integrity of hippocampal neurons. Transcriptomic sequencing of hippocampal tissue was performed to identify differentially expressed genes, which were subjected to Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Immunofluorescence analysis was used to detect the levels of Cd16, Cd32, Cd68 and Cd206 in APP/PS1 mice. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR), immunoblotting, and immunohistochemistry were employed to validate the relative expression of Vegf, Flt1, and Kdr proteins. Results In the Morris water maze, melatonin-treated APP/PS1 mice demonstrated a marked increase in platform crossings. Improved neuronal integrity in the hippocampus was observed through Haematoxylin&Eosin and Nissl staining. Transcriptomic sequencing of hippocampal tissue revealed 295 differentially expressed genes, which were significantly associated with 1091 GO terms and 30 KEGG pathways. Immunofluorescence analysis indicated that melatonin treatment notably reduced Cd16 and Cd32 levels while elevating Cd68 and Cd206 in APP/PS1 mice. Subsequent analyses via RT-qPCR, immunoblotting, and immunohistochemistry validated the increased relative expression of Vegf, Flt1, and Kdr proteins. Discussion Melatonin attenuates AD pathogenesis in APP/PS1 mice by promoting macrophage polarization via the Vegf signaling pathway, revealing a novel mechanism for AD prevention and treatment.
BACKGROUND:Essential tremor (ET) is the most common movement disorder in the elderly. Despite a close relationship between ET onset and age, it remains unclear whether ET reflects accelerated brain ageing or disease-specific structural changes. This study investigated whether ET is associated with accelerated global brain ageing or altered regional ageing patterns. METHODS:We studied 38 ET patients and 37 matched controls using 3 T structural and diffusion MRI alongside clinical assessments. Brain age and brain age gap (BAG; the difference between chronological and brain age) were estimated by a deep learning model. We analyzed group differences in global brain morphometry, and regional correlations between brain age and volumetric data. Regions demonstrating differential ageing in ET were combined into a composite metric to characterize disease-specific effects. RESULTS:Spatial patterns of brain ageing differed between ET and controls despite no evidence of globally accelerated ageing. In controls, brain age was associated with enlarged ventricles and diffuse cortical thinning, consistent with prototypical ageing. In contrast, ET showed strong negative associations between brain age and volumes specifically in the cerebellar cortex, thalami, and cortical tremor network. A composite metric comprising these regions demonstrated a significant interaction with group and predicted brain age, with ET patients showing volume reduction. CONCLUSIONS:ET is characterized by a distinct, disease-specific pattern of brain ageing rather than accelerated global ageing. This suggests that ET al.ters the spatial distribution of age-related structural changes, preferentially affecting the tremor network, and may help explain ET clinical heterogeneity.
