Administration of exosomes derived from mesenchymal stromal cells (MSCs) could improve some neurologic conditions by transferring functional biomolecules to recipient cells. Furthermore, exosomes ...from hypoxic progenitor cells exerted better therapeutic effects in organ injury through specific cargoes. However, there are no related reports about whether exosomes derived from MSCs or hypoxia‐preconditioned MSCs (PC‐MSCs) could prevent memory deficits in Alzheimer disease (AD). In this study, the exosomes derived from MSCs or PC‐MSCs were systemically administered to transgenic APP/PS1 mice. The expression of miR‐21 in MSCs was significantly increased after hypoxic treatment. Injection of exosomes from normoxic MSCs could rescue cognition and memory impairment according to results of the Morris water maze test, reduced plaque deposition, and Aβ levels in the brain; could decrease the activation of astrocytes and microglia; could down‐regulate proinflammatory cytokines (TNF‐α and IL‐1β); and could up‐regulate anti‐inflammatory cytokines (IL‐4 and ‐10) in AD mice, as well as reduce the activation of signal transducer and activator of transcription 3 (STAT3) and NF‐κB. Compared to the group administered exosomes from normoxic MSCs, in the group administered exosomes from PC‐MSCs, learning and memory capabilities were significantly improved; the plaque deposition and Aβ levels were lower, and expression of growth‐associated protein 43, synapsin 1, and IL‐10 was increased; and the levels of glial fibrillary acidic protein, ionized calcium‐binding adaptor molecule 1, TNF‐α, IL‐1β, and activation of STAT3 and NF‐κB were sharply decreased. More importantly, exosomes from PC‐MSCs effectively increased the level of miR‐21 in the brain of AD mice. Additionally, replenishment of miR‐21 restored the cognitive deficits in APP/PS1 mice and prevented pathologic features. Taken together, these findings suggest that exosomes from PC‐MSCs could improve the learning and memory capabilities of APP/PS1 mice, and that the underlying mechanism may lie in the restoration of synaptic dysfunction and regulation of inflammatory responses through regulation of miR‐21.—Cui, G.‐H., Wu, J., Mou, F.‐F., Xie, W.‐H., Wang, F.‐B., Wang, Q.‐L., Fang, J., Xu, Y.‐W., Dong, Y.‐R., Liu, J.‐R., Guo, H.‐D. Exosomes derived from hypoxia‐preconditioned mesenchymal stromal cells ameliorate cognitive decline by rescuing synaptic dysfunction and regulating inflammatory responses in APP/PS1 mice. FASEB J. 32, 654–668 (2018). www.fasebj.org
Exosomes are lipid-bilayer enclosed nano-sized vesicles that transfer functional cellular proteins, mRNA and miRNAs. Mesenchymal stem cells (MSCs) derived exosomes have been demonstrated to prevent ...memory deficits in the animal model of Alzheimer's disease (AD). However, the intravenously injected exosomes could be abundantly tracked in other organs except for the targeted regions in the brain. Here, we proposed the use of central nervous system-specific rabies viral glycoprotein (RVG) peptide to target intravenously-infused exosomes derived from MSCs (MSC-Exo) to the brain of transgenic APP/PS1 mice. MSC-Exo were conjugated with RVG through a DOPE-NHS linker.
RVG-tagged MSC-Exo exhibited improved targeting to the cortex and hippocampus after being administered intravenously. Compared with the group administered MSC-Exo, in the group administered RVG-conjugated MSC-Exo (MSC-RVG-Exo) plaque deposition and Aβ levels were sharply decreased and activation of astrocytes was obviously reduced. The brain targeted exosomes derived from MSCs was better than unmodified exosomes to improve cognitive function in APP/PS1 mice according to Morris water maze test. Additionally, although MSC-Exo injected intravenously reduced the expression of pro-inflammatory mediators TNF-α, IL-β, and IL-6, but the changes of anti-inflammatory factors IL-10 and IL-13 were not obvious. However, administration of MSC-RVG-Exo significantly reduced the levels of TNF-α, IL-β, and IL-6 while significantly raised the levels of IL-10, IL-4 and IL-13.
Taken together, our results demonstrated a novel method for increasing delivery of exosomes for treatment of AD. By targeting exosomes to the cortex and hippocampus of AD mouse, there was a significant improvement in learning and memory capabilities with reduced plaque deposition and Aβ levels, and normalized levels of inflammatory cytokines.
The trigeminal vascular system is an important part of the anatomical and physiological basis of migraine. The effective connectivity (EC) among the regions of interest (ROIs) in the trigeminal ...vascular system involved in migraine without aura (MWoA) remains unclear.
In this cross-sectional study, 48 patients (mean SD age 38.06 10.35 years; male, 14/48 29%) with MWoA during the interictal phase and 48 healthy controls of similar age and sex (mean SD age 38.96 10.96 years; male, 14/48 29%) underwent resting-state functional magnetic resonance imaging (fMRI). Dynamic causal modeling analysis was conducted to investigate directional EC among ROIs in the trigeminal vascular system including the bilateral brainstem, the primary somatosensory cortex (S1), the thalamus, and the insula.
Compared with the healthy control group, MWoA represented significantly reduced EC from the left brainstem (Brainstem.L) to the left insula (MWoA: mean SD -0.16 0.36; healthy controls: mean SD 0.11 0.41; P
= 0.021), reduced EC from the Brainstem.L to the right insula (MWoA: mean SD -0.15 0.39; healthy controls: mean SD 0.03 0.35; P
= 0.021), and decreased EC from the left thalamus (Thalamus.L) to the Brainstem.L (MWoA: mean SD -0.13 0.56; healthy controls: mean SD 0.10 0.45; P
= 0.021). Altered EC parameters were not significantly correlated with MWoA clinical data.
These results further provide increasing evidence that disturbed homeostasis of the trigeminovascular nociceptive pathway is involved in the pathophysiological mechanisms of migraine. Patients with MWoA exhibited a regional interaction distinct from healthy controls in the neural pathway of the Bilateral Insula-Brainstem.L-Thalamus.L, which may shed light on the future understanding of brain mechanisms for MWoA. Future brain-based interventions are suggested to consider the dysregulation in the Bilateral Insula-Brainstem.L-Thalamus.L circuits.
Neurovascular coupling (NVC) provides new insights into migraine, a neurological disorder impacting over one billion people worldwide. This study compared NVC and cerebral blood flow (CBF) in ...patients with migraine without aura (MwoA) and healthy controls. About 55 MwoA patients in the interictal phase and 40 age‐ and sex‐matched healthy controls underwent resting‐state functional magnetic resonance imaging and arterial spin‐labeling perfusion imaging scans. The CBF and resting‐state neuronal activity indicators, including the amplitudes of low‐frequency fluctuation (ALFF), regional homogeneity (ReHo), and degree centrality (DC), were calculated for each participant. The global and regional NVCs were assessed using cross‐voxel CBF‐neuronal activity correlations and CBF/neuronal activity ratios. Patients with MwoA showed increased CBF/ALFF ratios in the left media, superior and inferior frontal gyri, and anterior cingulate gyrus, increased CBF/DC ratios in the left middle and inferior frontal gyri, and increased CBF/ReHo ratios in the right corpus callosum and right posterior cingulate gyrus. Lower CBF/ALFF ratios in the right rectal gyrus, the left orbital gyrus, the right inferior frontal gyrus, and the right superior temporal gyrus were also found in the MwoA patients. Furthermore, the CBF/ALFF ratios in the inferior frontal and superior temporal gyri were positively correlated with the Headache Impact Test scores and Hamilton anxiety scale scores in the MwoA patients. These findings provide evidence for the theory that abnormal NVC contributes to MwoA.
Patients with migraine without aura showed an aberrant coupling between cerebral blood flow and neural activity, which is related to their clinical indicators.
Ischemic stroke (IS) is one of the most dangerous medical conditions resulting in high mortality and morbidity. The increased brain temperature after IS is closely related to prognosis, making it ...highly significant for the early diagnosis and the progression evaluation of IS. Herein, a temperature‐responsive near infrared (NIR) emissive lanthanide luminescence nanoparticle is developed for the early diagnosis and brain temperature detection of IS. After intravenous injection, the nanoparticles can pass through the damaged blood–brain barrier of the ischemic region, allowing the extravasation and enrichment of nanoparticles into the ischemic brain tissue. The NIR luminescence signals of the nanoparticles are used not only to judge the location and severity of the cerebral ischemic injury but also to report the brain temperature variation in the ischemic area through a visualized way. The results show that the designed nanoparticles can be used for the early diagnosis of ischemic stroke and minimally invasive temperature detection of cerebral ischemic tissues in transient middle cerebral artery occlusion mice model, which is expected to make the clinical diagnosis of ischemic stroke more rapid and convenient, more accurately evaluate the state of brain injury in stroke patients and also guide stroke hypothermia treatment.
This study introduces a temperature‐responsive, near infrared (NIR) emissive lanthanide‐doped nanoparticle for early diagnosis of ischemic stroke. By designing core–shell structure in the nanoparticle, energy transfers among lanthanide ions are modulated to achieve NIR signal‐based bioimaging and brain temperature sensing for ischemic injury localization and prognosis evaluation. This work provides inspirations in accelerating diagnosis process, enriching brain injury assessment and guiding hypothermia treatment.
Background
Increasing evidence has suggested that the cerebellum is associated with pain and migraine. In addition, the descending pain system of the brainstem is the major site of trigeminal pain ...processing and modulation and has been discussed as a main player in the pathophysiology of migraine. Cerebellar and brainstem structural changes associated with migraineurs remain to be further investigated.
Methods
Voxel-based morphometry (VBM) (50 controls, 50 migraineurs without aura (MWoAs)) and diffusion tensor imaging (DTI) (46 controls, 46 MWoAs) were used to assess cerebellum and brainstem anatomical alterations associated with MWoAs. We utilized a spatially unbiased infratentorial template toolbox (SUIT) to perform cerebellum and brainstem optimized VBM and DTI analysis. We extracted the average diffusion values from a probabilistic cerebellar white matter atlas to investigate whether MWoAs exhibited microstructure alterations in the cerebellar peduncle tracts.
Results
MWoAs showed decreased fractional anisotropy (FA) in the vermis VI extending to the bilateral lobules V and VI of the cerebellum. We also found higher axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD) in the right inferior cerebellum peduncle tract in MWoAs. MWoAs exhibited both reduced gray matter volume and increased AD, MD and RD in the spinal trigeminal nucleus (SpV).
Conclusion
MWoAs exhibited microstructural changes in the cerebellum and the local brainstem. These structural differences might contribute to dysfunction of the transmission and modulation of noxious information, trigeminal nociception, and conduction and integration of multimodal information in MWoAs. These findings further suggest involvement of the cerebellum and the brainstem in the pathology of migraine without aura.
Background
Migraine is a severe and disabling brain disorder, and the exact neurological mechanisms remain unclear. Migraineurs have altered pain perception, and headache attacks disrupt their ...sensory information processing and sensorimotor integration. The altered functional connectivity of sub-regions of sensorimotor brain areas with other brain cortex associated with migraine needs further investigation.
Methods
Forty-eight migraineurs without aura during the interictal phase and 48 age- and sex-matched healthy controls underwent resting-state functional magnetic resonance imaging scans. We utilized seed-based functional connectivity analysis to investigate whether patients exhibited abnormal functional connectivity between sub-regions of sensorimotor brain areas and cortex regions.
Results
We found that patients with migraineurs without aura exhibited disrupted functional connectivities between the sensorimotor areas and the visual cortex, temporal cortex, posterior parietal lobule, prefrontal areas, precuneus, cingulate gyrus, sensorimotor areas proper and cerebellum areas compared with healthy controls. In addition, the clinical data of the patients, such as disease duration, pain intensity and HIT-6 score, were negatively correlated with these impaired functional connectivities.
Conclusion
In patients with migraineurs without aura, the functional connectivities between the sensorimotor brain areas and other brain regions was reduced. These disrupted functional connectivities might contribute to abnormalities in visual processing, multisensory integration, nociception processing, spatial attention and intention and dysfunction in cognitive evaluation and modulation of pain. Recurrent headache attacks might lead to the disrupted network between primary motor cortex and temporal regions and between primary somatosensory cortex and temporal regions. Pain sensitivity and patient quality of life are closely tied to the abnormal functional connectivity between sensorimotor regions and other brain areas.
The platelet-to-lymphocyte ratio (PLR) is a new marker of atherosclerotic inflammation and has been identified as a predictive factor in cardiovascular diseases, but its significance in patients with ...acute ischaemic stroke (AIS) who have undergone intravenous thrombolysis (IVT) is still unknown.
Consecutive patients who were treated with IVT using recombinant tissue plasminogen activator (rtPA) for AIS were included from May 2012 to August 2018. The PLR was calculated according to platelet and lymphocyte counts within 24 h after thrombolysis therapy. Functional outcomes were assessed by the modified Rankin Scale (mRS) at 3 months after thrombolysis. Stroke severity was assessed by National Institutes of Health Stroke Scale (NIHSS) scores. The primary endpoint was an unfavorable outcome (mRS > 2), and the secondary endpoint was death at 3 months.
A total of 286 patients were included in the study. The median age was 69.5 (59.0-80.0) years, and 59.1% of patients were men. A total of 120 (42.0%) patients had an unfavorable outcome, and 38 (13.2%) died. Patients with an unfavorable outcome had significantly higher PLR values compared with those with a favorable outcome 172.5 (105.3-239.0) vs. 139 (97.0-194.5),
= 0.008, and the PLR values of the patients who died at 3 months were higher than those of the surviving patients 189.5 (127.5-289.0) vs. 142.0 (98.0-215.5),
= 0.006. After adjustment for other variables, the PLR was independently associated with the two endpoints: unfavorable outcome (OR 2.220, 95% CI 1.245-3.957,
= 0.007) and death (OR 2.825, 95% CI 1.050-7.601,
= 0.040) at 3 months after thrombolysis. In addition, PLR was correlated with the NIHSS score (R = 0.230,
< 0.001).
Higher PLR levels were independently associated with an unfavorable outcome and death at 3 months in AIS patients treated with IVT.
Currently, the relationship between household size and incident dementia, along with the underlying neurobiological mechanisms, remains unclear. This prospective cohort study was based on UK Biobank ...participants aged ≥ 50 years without a history of dementia. The linear and non-linear longitudinal association was assessed using Cox proportional hazards regression and restricted cubic spline models. Additionally, the potential mechanisms driven by brain structures were investigated by linear regression models. We included 275,629 participants (mean age at baseline 60.45 years SD 5.39). Over a mean follow-up of 9.5 years, 6031 individuals developed all-cause dementia. Multivariable analyses revealed that smaller household size was associated with an increased risk of all-cause dementia (HR, 1.06; 95% CI 1.02-1.09), vascular dementia (HR, 1.08; 95% CI 1.01-1.15), and non-Alzheimer's disease non-vascular dementia (HR, 1.09; 95% CI 1.03-1.14). No significant association was observed for Alzheimer's disease. Restricted cubic splines demonstrated a reversed J-shaped relationship between household size and all-cause and cause-specific dementia. Additionally, substantial associations existed between household size and brain structures. Our findings suggest that small household size is a risk factor for dementia. Additionally, brain structural differences related to household size support these associations. Household size may thus be a potential modifiable risk factor for dementia.
Long-term headache attacks may cause human brain network reorganization in patients with migraine. In the current study, we calculated the topologic properties of functional networks based on the ...Brainnetome atlas using graph theory analysis in 29 female migraineurs without aura (MWoA) and in 29 female age-matched healthy controls. Compared with controls, female MWoA exhibited that the network properties altered, and the nodal centralities decreased/increased in some brain areas. In particular, the right posterior insula and the left medial superior occipital gyrus of patients exhibited significantly decreased nodal centrality compared with healthy controls. Furthermore, female MWoA exhibited a disrupted functional network, and notably, the two sub-regions of the right posterior insula exhibited decreased functional connectivity with many other brain regions. The topological metrics of functional networks in female MWoA included alterations in the nodal centrality of brain regions and disrupted connections between pair regions primarily involved in the discrimination of sensory features of pain, pain modulation or processing and sensory integration processing. In addition, the posterior insula decreased the nodal centrality, and exhibited disrupted connectivity with many other brain areas in female migraineurs, which suggests that the posterior insula plays an important role in female migraine pathology.
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