Journal: J Cereb Blood Flow Metab

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Abstract

Regional hyperperfusion in older adults with objectively-defined subtle cognitive decline.

Thomas KR, Osuna JR, Weigand AJ, Edmonds EC, ... Bangen KJ, Alzheimer’s Disease Neuroimaging Initiative
Although cerebral blood flow (CBF) alterations are associated with Alzheimer\'s disease (AD), CBF patterns across prodromal stages of AD remain unclear. Therefore, we investigated patterns of regional CBF in 162 Alzheimer\'s Disease Neuroimaging Initiative participants characterized as cognitively unimpaired (CU; n = 80), objectively-defined subtle cognitive decline (Obj-SCD; n = 31), or mild cognitive impairment (MCI; n = 51). Arterial spin labeling MRI quantified regional CBF in a priori regions of interest: hippocampus, inferior temporal gyrus, inferior parietal lobe, medial orbitofrontal cortex, and rostral middle frontal gyrus. Obj-SCD participants had increased hippocampal and inferior parietal CBF relative to CU and MCI participants and increased inferior temporal CBF relative to MCI participants. CU and MCI groups did not differ in hippocampal or inferior parietal CBF, but CU participants had increased inferior temporal CBF relative to MCI participants. There were no CBF group differences in the two frontal regions. Thus, we found an inverted-U pattern of CBF signal across prodromal AD stages in regions susceptible to early AD pathology. Hippocampal and inferior parietal hyperperfusion in Obj-SCD may reflect early neurovascular dysregulation, whereby higher CBF is needed to maintain cognitive functioning relative to MCI participants, yet is also reflective of early cognitive inefficiencies that distinguish Obj-SCD from CU participants.



J Cereb Blood Flow Metab: 29 Apr 2021; 41:1001-1012
Thomas KR, Osuna JR, Weigand AJ, Edmonds EC, ... Bangen KJ, Alzheimer’s Disease Neuroimaging Initiative
J Cereb Blood Flow Metab: 29 Apr 2021; 41:1001-1012 | PMID: 32615887
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Abstract

Inhibition of eIF5A hypusination pathway as a new pharmacological target for stroke therapy.

Bourourou M, Gouix E, Melis N, Friard J, ... Tauc M, Blondeau N
In eukaryotes, the polyamine pathway generates spermidine that activates the hypusination of the translation factor eukaryotic initiation factor 5A (eIF5A). Hypusinated-eIF5A modulates translation, elongation, termination and mitochondrial function. Evidence in model organisms like drosophila suggests that targeting polyamines synthesis might be of interest against ischemia. However, the potential of targeting eIF5A hypusination in stroke, the major therapeutic challenge specific to ischemia, is currently unknown. Using in vitro models of ischemic-related stress, we documented that GC7, a specific inhibitor of a key enzyme in the eIF5A activation pathway, affords neuronal protection. We identified the preservation of mitochondrial function and thereby the prevention of toxic ROS generation as major processes of GC7 protection. To represent a thoughtful opportunity of clinical translation, we explored whether GC7 administration reduces the infarct volume and functional deficits in an in vivo transient focal cerebral ischemia (tFCI) model in mice. A single GC7 pre- or post-treatment significantly reduces the infarct volume post-stroke. Moreover, GC7-post-treatment significantly improves mouse performance in the rotarod and Morris water-maze, highlighting beneficial effects on motor and cognitive post-stroke deficits. Our results identify the targeting of the polyamine-eIF5A-hypusine axis as a new therapeutic opportunity and new paradigm of research in stroke and ischemic diseases.



J Cereb Blood Flow Metab: 29 Apr 2021; 41:1080-1090
Bourourou M, Gouix E, Melis N, Friard J, ... Tauc M, Blondeau N
J Cereb Blood Flow Metab: 29 Apr 2021; 41:1080-1090 | PMID: 32615885
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Abstract

D-Glucose uptake and clearance in the tauopathy Alzheimer\'s disease mouse brain detected by on-resonance variable delay multiple pulse MRI.

Chen L, Wei Z, Chan KW, Li Y, ... Li T, Xu J
In this study, we applied on-resonance variable delay multiple pulse (onVDMP) MRI to study D-glucose uptake in a mouse model of Alzheimer\'s disease (AD) tauopathy and demonstrated its feasibility in discriminating AD mice from wild-type mice. The D-glucose uptake in the cortex of AD mice (1.70 ± 1.33%) was significantly reduced compared to that of wild-type mice (5.42 ± 0.70%, p = 0.0051). Also, a slower D-glucose uptake rate was found in the cerebrospinal fluid (CSF) of AD mice (0.08 ± 0.01 min-1) compared to their wild-type counterpart (0.56 ± 0.1 min-1, p < 0.001), which suggests the presence of an impaired glucose transporter on both blood-brain and blood-CSF barriers of these AD mice. Clearance of D-glucose was observed in the CSF of wild-type mice but not AD mice, which suggests dysfunction of the glymphatic system in the AD mice. The results in this study indicate that onVDMP MRI could be a cost-effective and widely available method for simultaneously evaluating glucose transporter and glymphatic function of AD. This study also suggests that tau protein affects the D-glucose uptake and glymphatic impairment in AD at a time point preceding neurofibrillary tangle pathology.



J Cereb Blood Flow Metab: 29 Apr 2021; 41:1013-1025
Chen L, Wei Z, Chan KW, Li Y, ... Li T, Xu J
J Cereb Blood Flow Metab: 29 Apr 2021; 41:1013-1025 | PMID: 32669023
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Abstract

Differential contribution of excitatory and inhibitory neurons in shaping neurovascular coupling in different epileptic neural states.

Lim HK, You N, Bae S, Kang BM, ... Kim SG, Suh M
Understanding the neurovascular coupling (NVC) underlying hemodynamic changes in epilepsy is crucial to properly interpreting functional brain imaging signals associated with epileptic events. However, how excitatory and inhibitory neurons affect vascular responses in different epileptic states remains unknown. We conducted real-time in vivo measurements of cerebral blood flow (CBF), vessel diameter, and excitatory and inhibitory neuronal calcium signals during recurrent focal seizures. During preictal states, decreases in CBF and arteriole diameter were closely related to decreased γ-band local field potential (LFP) power, which was linked to relatively elevated excitatory and reduced inhibitory neuronal activity levels. Notably, this preictal condition was followed by a strengthened ictal event. In particular, the preictal inhibitory activity level was positively correlated with coherent oscillating activity specific to inhibitory neurons. In contrast, ictal states were characterized by elevated synchrony in excitatory neurons. Given these findings, we suggest that excitatory and inhibitory neurons differentially contribute to shaping the ictal and preictal neural states, respectively. Moreover, the preictal vascular activity, alongside with the γ-band, may reflect the relative levels of excitatory and inhibitory neuronal activity, and upcoming ictal activity. Our findings provide useful insights into how perfusion signals of different epileptic states are related in terms of NVC.



J Cereb Blood Flow Metab: 29 Apr 2021; 41:1145-1161
Lim HK, You N, Bae S, Kang BM, ... Kim SG, Suh M
J Cereb Blood Flow Metab: 29 Apr 2021; 41:1145-1161 | PMID: 32669018
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Abstract

HDAC inhibition reduces white matter injury after intracerebral hemorrhage.

Yang H, Ni W, Wei P, Li S, ... Zhou L, Gu Y
Inhibition of histone deacetylases (HDACs) has been shown to reduce inflammation and white matter damage after various forms of brain injury via modulation of microglia/macrophage polarization. Previously we showed that the HDAC inhibitor scriptaid could attenuate white matter injury (WMI) after ICH. To access whether modulation of microglia/macrophage polarization might underlie this protection, we investigated the modulatory role of HDAC2 in microglia/macrophage polarization in response to WMI induced by intracerebral hemorrhage (ICH) and in primary microglia and oligodendrocyte co-cultures. HDAC2 activity was inhibited via conditional knockout of the Hdac2 gene in microglia or via administration of scriptaid. Conditional knockout of the Hdac2 gene in microglia and HDAC inhibition with scriptaid both improved neurological functional recovery and reduced WMI after ICH. Additionally, HDAC inhibition shifted microglia/macrophage polarization toward the M2 phenotype and reduced proinflammatory cytokine secretion after ICH in vivo. In vitro, a transwell co-culture model of microglia and oligodendrocytes also demonstrated that the HDAC inhibitor protected oligodendrocytes by modulating microglia polarization and mitigating neuroinflammation. Moreover, we found that scriptaid decreased the expression of pJAK2 and pSTAT1 in cultured microglia when stimulated with hemoglobin. Thus, HDAC inhibition ameliorated ICH-mediated neuroinflammation and WMI by modulating microglia/macrophage polarization.



J Cereb Blood Flow Metab: 29 Apr 2021; 41:958-974
Yang H, Ni W, Wei P, Li S, ... Zhou L, Gu Y
J Cereb Blood Flow Metab: 29 Apr 2021; 41:958-974 | PMID: 32703113
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Abstract

Efficient isolation of brain capillary from a single frozen mouse brain for protein expression analysis.

Ogata S, Ito S, Masuda T, Ohtsuki S
Isolated brain capillaries are essential for analyzing the changes of protein expressions at the blood-brain barrier (BBB) under pathological conditions. The standard brain capillary isolation methods require the use of at least five mouse brains in order to obtain a sufficient amount and purity of brain capillaries. The purpose of this study was to establish a brain capillary isolation method from a single mouse brain for protein expression analysis. We successfully isolated brain capillaries from a single frozen mouse brain by using a bead homogenizer in the brain homogenization step and combination of cell strainers and glass beads in the purification step. Western blot and proteomic analysis showed that proteins expressed at the BBB in mouse brain capillaries isolated by the developed method were more enriched than those isolated from a pool of five mouse brains by the standard method. By using the developed method, we further verified the changes in expression of BBB proteins in Glut1-deficient mouse. The developed method is useful for the analysis of various mice models with low numbers and enables us to understand, in more detail, the physiology and pathology of BBB.



J Cereb Blood Flow Metab: 29 Apr 2021; 41:1026-1038
Ogata S, Ito S, Masuda T, Ohtsuki S
J Cereb Blood Flow Metab: 29 Apr 2021; 41:1026-1038 | PMID: 32703112
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Abstract

Deletion of ubiquitin ligase Nedd4l exacerbates ischemic brain damage.

Kim T, Chokkalla AK, Vemuganti R
Ubiquitination by Nedd4 (neuronally expressed developmentally downregulated 4) family of HECT type E3 ligases plays a key role in degrading misfolded and damaged proteins, and its disruption leads to neurodegeneration. Parkinson\'s disease-causing protein α-Synuclein (α-Syn) is ubiquitinated by the Nedd4 family and degraded by endosomes. Nedd4l is the only Nedd4 homolog that showed upregulation in post-stroke surviving cortical neurons where it correlated with neuroprotection. We tested the role of Nedd4l after stroke by subjecting the Nedd4l-/- mice to transient middle cerebral artery occlusion. Focal ischemia significantly increased Nedd4l expression and poly-ubiquitinated α-Syn levels, and knockout of Nedd4l reduced post-ischemic poly-ubiquitinated α-Syn that is majorly located in the peri-infarct neurons. Co-immunoprecipitation further shows that focal ischemia enhances the α-Syn-Nedd4l interaction resulting in increased ubiquitination of α-Syn. Nedd4l knockout mice (n = 7 mice/group) showed exacerbated post-ischemic motor dysfunction manifested by decreased time on the rotarod and increased number of foot faults, and significantly increased ischemic brain damage. This suggests that Nedd4l might be a potential therapeutic target to minimize α-Syn-mediated toxicity after cerebral ischemia.



J Cereb Blood Flow Metab: 29 Apr 2021; 41:1058-1066
Kim T, Chokkalla AK, Vemuganti R
J Cereb Blood Flow Metab: 29 Apr 2021; 41:1058-1066 | PMID: 32703111
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Abstract

Accumulation of PSA-NCAM marks nascent neurodegeneration in the dorsal hippocampus after neonatal hypoxic-ischemic brain injury in mice.

Chavez-Valdez R, Lechner C, Emerson P, Northington FJ, Martin LJ
Neonatal hypoxia-ischemia (nHI) disrupts hippocampal GABAergic development leading to memory deficits in mice. Polysialic-acid neural-cell adhesion molecule (PSA-NCAM) developmentally declines to trigger GABAergic maturation. We hypothesized that nHI changes PSA-NCAM abundance and cellular distribution, impairing GABAergic development, and marking nascent neurodegeneration. Cell degeneration, atrophy, and PSA-NCAM immunoreactivity (IR) were measured in CA1 of nHI-injured C57BL6 mice related to: (i) cellular subtype markers; (ii) GAD65/67 and synatophysin (SYP), pre-synaptic markers; (iii) phospho-Ser396Tau, cytoskeletal marker; and (iv) GAP43, axonalregeneration marker. PSA-NCAM IR was minimal in CA1 of shams at P11. After nHI, PSA-NCAM IR was increased in injured pyramidal cells (PCs), minimal in parvalbumin (PV)+INs, and absent in glia. PSA-NCAM IR correlated with injury severity and became prominent in perikaryal cytoplasm at P18. GAD65/67 and SYP IRs only weakly related to PSA-NCAM after nHI. Injured phospho-Ser396Tau+ PCs and PV+INs variably co-expressed PSA-NCAM at P40. While PCs with cytoplasmic marginalized PSA-NCAM had increased perisomatic GAP43, those with perikaryal cytoplasmic PSA-NCAM had minimal GAP43. PSA-NCAM increased in serum of nHI-injured mice. Increased PSA-NCAM is likely a generic acute response to nHI brain injury. PSA-NCAM aberrant cellular localization may aggravate neuronal degeneration. The significance of PSA-NCAM as a biomarker of recovery from nHI and nascent neurodegeneration needs further study.



J Cereb Blood Flow Metab: 29 Apr 2021; 41:1039-1057
Chavez-Valdez R, Lechner C, Emerson P, Northington FJ, Martin LJ
J Cereb Blood Flow Metab: 29 Apr 2021; 41:1039-1057 | PMID: 32703109
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Abstract

Binding of the synaptic vesicle radiotracer [C]UCB-J is unchanged during functional brain activation using a visual stimulation task.

Smart K, Liu H, Matuskey D, Chen MK, ... Huang Y, Carson RE
The positron emission tomography radioligand [11C]UCB-J binds to synaptic vesicle glycoprotein 2 A (SV2A), a regulator of vesicle release. Increased neuronal firing could potentially affect tracer concentrations if binding site availability is altered during vesicle exocytosis. This study assessed whether physiological brain activation induces changes in [11C]UCB-J tissue influx (K1), volume of distribution (VT), or binding potential (BPND). Healthy volunteers (n = 7) underwent 60-min [11C]UCB-J PET scans at baseline and during intermittent presentation of 8-Hz checkerboard visual stimulation. Sensitivity to intermittent changes in kinetic parameters was assessed in simulations, and visual stimulation was repeated using functional magnetic resonance imaging to characterize neural responses. VT  and K1 were determined using the one-tissue compartment model and BPND using the simplified reference tissue model. In primary visual cortex, K1 increased 34.3 ± 15.5% (p = 0.001) during stimulation, with no change in other regions (ps>0.12). K1 change was correlated with fMRI BOLD response (r = 0.77, p = 0.043). There was no change in VT (-3.9 ± 8.8%, p =0.33) or BPND (-0.2 ± 9.6%, p =0.94) in visual cortex nor other regions (ps>0.19). Therefore, despite robust increases in regional tracer influx due to blood flow increases, binding measures were unchanged during stimulation. [11C]UCB-J VT and BPND are likely to be stable in vivo measures of synaptic density.



J Cereb Blood Flow Metab: 29 Apr 2021; 41:1067-1079
Smart K, Liu H, Matuskey D, Chen MK, ... Huang Y, Carson RE
J Cereb Blood Flow Metab: 29 Apr 2021; 41:1067-1079 | PMID: 32757741
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Abstract

Cardiac arrest and resuscitation activates the hypothalamic-pituitary-adrenal axis and results in severe immunosuppression.

Zhao Q, Shen Y, Li R, Wu J, ... Zhang W, Yang W
In patients who are successfully resuscitated after initial cardiac arrest (CA), mortality and morbidity rates are high, due to ischemia/reperfusion injury to the whole body including the nervous and immune systems. How the interactions between these two critical systems contribute to post-CA outcome remains largely unknown. Using a mouse model of CA and cardiopulmonary resuscitation (CA/CPR), we demonstrate that CA/CPR induced neuroinflammation in the brain, in particular, a marked increase in pro-inflammatory cytokines, which subsequently activated the hypothalamic-pituitary-adrenal (HPA) axis. Importantly, this activation was associated with a severe immunosuppression phenotype after CA. The phenotype was characterized by a striking reduction in size of lymphoid organs accompanied by a massive loss of immune cells and reduced immune function of splenic lymphocytes. The mechanistic link between post-CA immunosuppression and the HPA axis was substantiated, as we discovered that glucocorticoid treatment, which mimics effects of the activated HPA axis, exacerbated post-CA immunosuppression, while RU486 treatment, which suppresses its effects, significantly mitigated lymphopenia and lymphoid organ atrophy and improved CA outcome. Taken together, targeting the HPA axis could be a viable immunomodulatory therapeutic to preserve immune homeostasis after CA/CPR and thus improve prognosis of post-resuscitation CA patients.



J Cereb Blood Flow Metab: 29 Apr 2021; 41:1091-1102
Zhao Q, Shen Y, Li R, Wu J, ... Zhang W, Yang W
J Cereb Blood Flow Metab: 29 Apr 2021; 41:1091-1102 | PMID: 32787543
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Abstract

Diffuse white matter loss in a transgenic rat model of cerebral amyloid angiopathy.

Lee H, Xu F, Liu X, Koundal S, ... Van Nostrand WE, Benveniste H
Diffuse white matter (WM) disease is highly prevalent in elderly with cerebral small vessel disease (cSVD). In humans, cSVD such as cerebral amyloid angiopathy (CAA) often coexists with Alzheimer\'s disease imposing a significant impediment for characterizing their distinct effects on WM. Here we studied the burden of age-related CAA pathology on WM disease in a novel transgenic rat model of CAA type 1 (rTg-DI). A cohort of rTg-DI and wild-type rats was scanned longitudinally using MRI for characterization of morphometry, cerebral microbleeds (CMB) and WM integrity. In rTg-DI rats, a distinct pattern of WM loss was observed at 9 M and 11 M. MRI also revealed manifestation of small CMB in thalamus at 6 M, which preceded WM loss and progressively enlarged until the moribund disease stage. Histology revealed myelin loss in the corpus callosum and thalamic CMB in all rTg-DI rats, the latter of which manifested in close proximity to occluded and calcified microvessels. The quantitation of CAA load in rTg-DI rats revealed that the most extensive microvascular Aβ deposition occurred in the thalamus. For the first time using in vivo MRI, we show that CAA type 1 pathology alone is associated with a distinct pattern of WM loss.



J Cereb Blood Flow Metab: 29 Apr 2021; 41:1103-1118
Lee H, Xu F, Liu X, Koundal S, ... Van Nostrand WE, Benveniste H
J Cereb Blood Flow Metab: 29 Apr 2021; 41:1103-1118 | PMID: 32791876
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Abstract

Impaired response of cerebral oxygen metabolism to visual stimulation in Huntington\'s disease.

Klinkmueller P, Kronenbuerger M, Miao X, Bang J, ... Ross CA, Hua J
Huntington\'s disease (HD) is a neurodegenerative disease caused by a CAG triplet repeat expansion in the Huntingtin gene. Metabolic and microvascular abnormalities in the brain may contribute to early physiological changes that subserve the functional impairments in HD. This study is intended to investigate potential abnormality in dynamic changes in cerebral blood volume (CBV) and cerebral blood flow (CBF), and cerebral metabolic rate of oxygen (CMRO2) in the brain in response to functional stimulation in premanifest and early manifest HD patients. A recently developed 3-D-TRiple-acquisition-after-Inversion-Preparation magnetic resonance imaging (MRI) approach was used to measure dynamic responses in CBV, CBF, and CMRO2 during visual stimulation in one single MRI scan. Experiments were conducted in 23 HD patients and 16 healthy controls. Decreased occipital cortex CMRO2 responses were observed in premanifest and early manifest HD patients compared to controls (P < 0.001), correlating with the CAG-Age Product scores in these patients (R2 = 0.4, P = 0.001). The results suggest the potential value of this reduced CMRO2 response during visual stimulation as a biomarker for HD and may illuminate the role of metabolic alterations in the pathophysiology of HD.



J Cereb Blood Flow Metab: 29 Apr 2021; 41:1119-1130
Klinkmueller P, Kronenbuerger M, Miao X, Bang J, ... Ross CA, Hua J
J Cereb Blood Flow Metab: 29 Apr 2021; 41:1119-1130 | PMID: 32807001
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Abstract

MiR-17-92 enriched exosomes derived from multipotent mesenchymal stromal cells enhance axon-myelin remodeling and motor electrophysiological recovery after stroke.

Xin H, Liu Z, Buller B, Li Y, ... Zhang ZG, Chopp M
MiR-17-92 cluster enriched exosomes derived from multipotent mesenchymal stromal cells (MSCs) increase functional recovery after stroke. Here, we investigate the mechanisms underlying this recovery. At 24 h (h) post transient middle cerebral artery occlusion, rats received control liposomes or exosomes derived from MSCs infected with pre-miR-17-92 expression lentivirus (Exo-miR-17-92+) or control lentivirus (Exo-Con) intravenously. Compared to the liposomes, exosomes significantly reduced the intracortical microstimulation threshold current of the contralateral cortex for evoking impaired forelimb movements (day 21), increased the neurite and myelin density in the ischemic boundary area, and contralesional axonal sprouting into the caudal forelimb area of ipsilateral side and in the denervated spinal cord (day 28), respectively. The Exo-miR-17-92+ further enhanced axon-myelin remodeling and electrophysiological recovery compared with the EXO-Con. Ex vivo cultured rat brain slice data showed that myelin and neuronal fiber density were significantly increased by Exo-miR-17-92+, while significantly inhibited by application of the PI3K/Akt/mTOR pathway inhibitors. Our studies suggest that the miR-17-92 cluster enriched MSC exosomes enhanced neuro-functional recovery of stroke may be attributed to an increase of axonal extension and myelination, and this enhanced axon-myelin remodeling may be mediated in part via the activation of the PI3K/Akt/mTOR pathway induced by the downregulation of PTEN.



J Cereb Blood Flow Metab: 29 Apr 2021; 41:1131-1144
Xin H, Liu Z, Buller B, Li Y, ... Zhang ZG, Chopp M
J Cereb Blood Flow Metab: 29 Apr 2021; 41:1131-1144 | PMID: 32811262
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Abstract

Subarachnoid hemorrhage leads to early and persistent functional connectivity and behavioral changes in mice.

Chung DY, Oka F, Jin G, Harriott A, ... Whalen MJ, Ayata C
Aneurysmal subarachnoid hemorrhage (SAH) leads to significant long-term cognitive deficits, which can be associated with alterations in resting state functional connectivity (RSFC). However, modalities such as fMRI-which is commonly used to assess RSFC in humans-have practical limitations in small animals. Therefore, we used non-invasive optical intrinsic signal imaging to determine the effect of SAH on RSFC in mice up to three months after prechiasmatic blood injection. We assessed Morris water maze (MWM), open field test (OFT), Y-maze, and rotarod performance from approximately two weeks to three months after SAH. Compared to sham, we found that SAH reduced motor, retrosplenial, and visual seed-based connectivity indices. These deficits persisted in retrosplenial and visual cortex seeds at three months. Seed-to-seed analysis confirmed early attenuation of correlation coefficients in SAH mice, which persisted in predominantly posterior network connections at later time points. Seed-independent global and interhemispheric indices of connectivity revealed decreased correlations following SAH for at least one month. SAH led to MWM hidden platform and OFT deficits at two weeks, and Y-maze deficits for at least three months, without altering rotarod performance. In conclusion, experimental SAH leads to early and persistent alterations both in hemodynamically derived measures of RSFC and in cognitive performance.



J Cereb Blood Flow Metab: 29 Apr 2021; 41:975-985
Chung DY, Oka F, Jin G, Harriott A, ... Whalen MJ, Ayata C
J Cereb Blood Flow Metab: 29 Apr 2021; 41:975-985 | PMID: 32936728
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Abstract

Brain amyloid and vascular risk are related to distinct white matter hyperintensity patterns.

Pålhaugen L, Sudre CH, Tecelao S, Nakling A, ... Selnes P, Fladby T
White matter hyperintensities (WMHs) are associated with vascular risk and Alzheimer\'s disease. In this study, we examined relations between WMH load and distribution, amyloid pathology and vascular risk in 339 controls and cases with either subjective (SCD) or mild cognitive impairment (MCI). Regional deep (DWMH) and periventricular (PWMH) WMH loads were determined using an automated algorithm. We stratified on Aβ1-42 pathology (Aβ+/-) and analyzed group differences, as well as associations with Framingham Risk Score for cardiovascular disease (FRS-CVD) and age. Occipital PWMH (p = 0.001) and occipital DWMH (p = 0.003) loads were increased in SCD-Aβ+ compared with Aβ- controls. In MCI-Aβ+ compared with Aβ- controls, there were differences in global WMH (p = 0.003), as well as occipital DWMH (p = 0.001) and temporal DWMH (p = 0.002) loads. FRS-CVD was associated with frontal PWMHs (p = 0.003) and frontal DWMHs (p = 0.005), after adjusting for age. There were associations between global and all regional WMH loads and age. In summary, posterior WMH loads were increased in SCD-Aβ+ and MCI-Aβ+ cases, whereas frontal WMHs were associated with vascular risk. The differences in WMH topography support the use of regional WMH load as an early-stage marker of etiology.



J Cereb Blood Flow Metab: 29 Apr 2021; 41:1162-1174
Pålhaugen L, Sudre CH, Tecelao S, Nakling A, ... Selnes P, Fladby T
J Cereb Blood Flow Metab: 29 Apr 2021; 41:1162-1174 | PMID: 32955960
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Abstract

Metabolic underpinnings of activated and deactivated cortical areas in human brain.

Koush Y, de Graaf RA, Kupers R, Dricot L, ... Rothman DL, Hyder F
Neuroimaging with functional MRI (fMRI) identifies activated and deactivated brain regions in task-based paradigms. These patterns of (de)activation are altered in diseases, motivating research to understand their underlying biochemical/biophysical mechanisms. Essentially, it remains unknown how aerobic metabolism of glucose to lactate (aerobic glycolysis) and excitatory-inhibitory balance of glutamatergic and GABAergic neuronal activities vary in these areas. In healthy volunteers, we investigated metabolic distinctions of activating visual cortex (VC, a task-positive area) using a visual task and deactivating posterior cingulate cortex (PCC, a task-negative area) using a cognitive task. We used fMRI-guided J-edited functional MRS (fMRS) to measure lactate, glutamate plus glutamine (Glx) and γ-aminobutyric acid (GABA), as indicators of aerobic glycolysis and excitatory-inhibitory balance, respectively. Both lactate and Glx increased upon activating VC, but did not change upon deactivating PCC. Basal GABA was negatively correlated with BOLD responses in both brain areas, but during functional tasks GABA decreased in VC upon activation and GABA increased in PCC upon deactivation, suggesting BOLD responses in relation to baseline are impacted oppositely by task-induced inhibition. In summary, opposite relations between BOLD response and GABAergic inhibition, and increases in aerobic glycolysis and glutamatergic activity distinguish the BOLD response in (de)activated areas.



J Cereb Blood Flow Metab: 29 Apr 2021; 41:986-1000
Koush Y, de Graaf RA, Kupers R, Dricot L, ... Rothman DL, Hyder F
J Cereb Blood Flow Metab: 29 Apr 2021; 41:986-1000 | PMID: 33472521
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Abstract

Microvascular changes associated with epilepsy: A narrative review.

van Lanen RH, Melchers S, Hoogland G, Schijns OE, ... Haeren RH, Rijkers K
The blood-brain barrier (BBB) is dysfunctional in temporal lobe epilepsy (TLE). In this regard, microvascular changes are likely present. The aim of this review is to provide an overview of the current knowledge on microvascular changes in epilepsy, and includes clinical and preclinical evidence of seizure induced angiogenesis, barriergenesis and microcirculatory alterations. Anatomical studies show increased microvascular density in the hippocampus, amygdala, and neocortex accompanied by BBB leakage in various rodent epilepsy models. In human TLE, a decrease in afferent vessels, morphologically abnormal vessels, and an increase in endothelial basement membranes have been observed. Both clinical and experimental evidence suggests that basement membrane changes, such as string vessels and protrusions, indicate and visualize a misbalance between endothelial cell proliferation and barriergenesis. Vascular endothelial growth factor (VEGF) appears to play a crucial role. Following an altered vascular anatomy, its physiological functioning is affected as expressed by neurovascular decoupling that subsequently leads to hypoperfusion, disrupted parenchymal homeostasis and potentially to seizures\". Thus, epilepsy might be a condition characterized by disturbed cerebral microvasculature in which VEGF plays a pivotal role. Additional physiological data from patients is however required to validate findings from models and histological studies on patient biopsies.



J Cereb Blood Flow Metab: 16 Apr 2021:271678X211010388; epub ahead of print
van Lanen RH, Melchers S, Hoogland G, Schijns OE, ... Haeren RH, Rijkers K
J Cereb Blood Flow Metab: 16 Apr 2021:271678X211010388; epub ahead of print | PMID: 33866850
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Abstract

Magnetic resonance imaging-based changes in vascular morphology and cerebral perfusion in subacute ischemic stroke.

Kufner A, Khalil AA, Galinovic I, Kellner E, ... Endres M, Nave AH
MRI-based vessel size imaging (VSI) allows for in-vivo assessment of cerebral microvasculature and perfusion. This exploratory analysis of vessel size (VS) and density (Q; both assessed via VSI) in the subacute phase of ischemic stroke involved sixty-two patients from the BAPTISe cohort (\'Biomarkers And Perfusion--Training-Induced changes after Stroke\') nested within a randomized controlled trial (intervention: 4-week training vs. relaxation). Relative VS, Q, cerebral blood volume (rCBV) and -flow (rCBF) were calculated for: ischemic lesion, perilesional tissue, and region corresponding to ischemic lesion on the contralateral side (mirrored lesion). Linear mixed-models detected significantly increased rVS and decreased rQ within the ischemic lesion compared to the mirrored lesion (coefficient[standard error]: 0.2[0.08] p = 0.03 and -1.0[0.3] p = 0.02, respectively); lesion rCBF and rCBV were also significantly reduced. Mixed-models did not identify time-to-MRI, nor training as modifying factors in terms of rVS or rQ up to two months post-stroke. Larger lesion VS was associated with larger lesion volumes (β 34, 95%CI 6.2-62; p = 0.02) and higher baseline NIHSS (β 3.0, 95%CI 0.49-5.3;p = 0.02), but was not predictive of six-month outcome. In summary, VSI can assess the cerebral microvasculature and tissue perfusion in the subacute phases of ischemic stroke, and may carry relevant prognostic value in terms of lesion volume and stroke severity.



J Cereb Blood Flow Metab: 16 Apr 2021:271678X211010071; epub ahead of print
Kufner A, Khalil AA, Galinovic I, Kellner E, ... Endres M, Nave AH
J Cereb Blood Flow Metab: 16 Apr 2021:271678X211010071; epub ahead of print | PMID: 33866849
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Abstract

Hemodynamic and structural brain measures in high and low sedentary older adults.

Maasakkers CM, Thijssen DH, Knight SP, Newman L, ... Claassen JA, Looze C
Due to its cardiovascular effects sedentary behaviour might impact cerebrovascular function in the long term, affecting cerebrovascular regulatory mechanisms and perfusion levels. Consequently this could underly potential structural brain abnormalities associated with cognitive decline. We therefore assessed the association between sedentary behaviour and brain measures of cerebrovascular perfusion and structural abnormalities in community-dwelling older adults. Using accelerometery (GENEActiv) data from The Irish Longitudinal Study on Ageing (TILDA) we categorised individuals by low- and high-sedentary behaviour (≤8 vs >8 hours/day). We examined prefrontal haemoglobin oxygenation levels using Near-Infrared Spectroscopy during rest and after an orthostatic challenge in 718 individuals (66 ± 8 years, 52% female). Global grey matter cerebral blood flow, total grey and white matter volume, total and subfield hippocampal volumes, cortical thickness, and white matter hyperintensities were measured using arterial spin labelling, T1, and FLAIR MRI in 86 individuals (72 ± 6 years, 55% female). While no differences in prefrontal or global cerebral hemodynamics were found between groups, high-sedentary individuals showed lower hippocampal volumes and increased white matter hyperintensities compared to their low-sedentary counterparts. Since these structural cerebral abnormalities are associated with cognitive decline and Alzheimer\'s disease, future work exploring the causal pathways underlying these differences is needed.



J Cereb Blood Flow Metab: 16 Apr 2021:271678X211009382; epub ahead of print
Maasakkers CM, Thijssen DH, Knight SP, Newman L, ... Claassen JA, Looze C
J Cereb Blood Flow Metab: 16 Apr 2021:271678X211009382; epub ahead of print | PMID: 33866848
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Impact:
Abstract

Neurovascular coupling dysfunction in end-stage renal disease patients related to cognitive impairment.

Li P, Mu J, Ma X, Ding D, ... Liu J, Zhang M
We aimed to investigate the neurovascular coupling (NVC) dysfunction in end-stage renal disease (ESRD) patients related with cognitive impairment. Twenty-five ESRD patients and 22 healthy controls were enrolled. To assess the NVC dysfunctional pattern, resting-state functional MRI and arterial spin labeling were explored to estimate the coupling of spontaneous neuronal activity and cerebral blood perfusion based on amplitude of low-frequency fluctuation (ALFF)-cerebral blood flow (CBF), fractional ALFF (fALFF)-CBF, regional homogeneity (ReHo)-CBF, and degree centrality (DC)-CBF correlation coefficients. Multivariate partial least-squares correlation and mediation analyses were used to evaluate the relationship among NVC dysfunctional pattern, cognitive impairment and clinical characteristics. The NVC dysfunctional patterns in ESRD patients were significantly decreased in 34 brain regions compared with healthy controls. The decreased fALFF-CBF coefficients in the cingulate gyrus (CG) were associated positively with lower kinetic transfer/volume urea (Kt/V) and lower short-term memory scores, and were negatively associated with higher serum urea. The relationship between Kt/V and memory deficits of ESRD patients was partially mediated by the fALFF-CBF alteration of the CG. These findings reveal the NVC dysfunction may be a potential neural mechanism for cognitive impairment in ESRD. The regional NVC dysfunction may mediate the impact of dialysis adequacy on memory function.



J Cereb Blood Flow Metab: 13 Apr 2021:271678X211007960; epub ahead of print
Li P, Mu J, Ma X, Ding D, ... Liu J, Zhang M
J Cereb Blood Flow Metab: 13 Apr 2021:271678X211007960; epub ahead of print | PMID: 33853410
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Abstract

Assessing cerebral arterial pulse wave velocity using 4D flow MRI.

Björnfot C, Garpebring A, Qvarlander S, Malm J, Eklund A, Wåhlin A
Intracranial arterial stiffening is a potential early marker of emerging cerebrovascular dysfunction and could be mechanistically involved in disease processes detrimental to brain function via several pathways. A prominent consequence of arterial wall stiffening is the increased velocity at which the systolic pressure pulse wave propagates through the vasculature. Previous non-invasive measurements of the pulse wave propagation have been performed on the aorta or extracranial arteries with results linking increased pulse wave velocity to brain pathology. However, there is a lack of intracranial \"target-organ\" measurements. Here we present a 4D flow MRI method to estimate pulse wave velocity in the intracranial vascular tree. The method utilizes the full detectable branching structure of the cerebral vascular tree in an optimization framework that exploits small temporal shifts that exists between waveforms sampled at varying depths in the vasculature. The method is shown to be stable in an internal consistency test, and of sufficient sensitivity to robustly detect age-related increases in intracranial pulse wave velocity.



J Cereb Blood Flow Metab: 13 Apr 2021:271678X211008744; epub ahead of print
Björnfot C, Garpebring A, Qvarlander S, Malm J, Eklund A, Wåhlin A
J Cereb Blood Flow Metab: 13 Apr 2021:271678X211008744; epub ahead of print | PMID: 33853409
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Abstract

Plasminogen deficiency causes reduced angiogenesis and behavioral recovery after stroke in mice.

Fang J, Chopp M, Xin H, Zhang L, ... He L, Liu Z
Plasminogen is involved in the process of angiogenesis; however, the underlying mechanism is unclear. Here, we investigated the potential contribution of plasmin/plasminogen in mediating angiogenesis and thereby contributing to functional recovery post-stroke. Wild-type plasminogen naive (Plg+/+) mice and plasminogen knockout (Plg-/-) mice were subjected to unilateral permanent middle cerebral artery occlusion (MCAo). Blood vessels were labeled with FITC-dextran. Functional outcomes, and cerebral vessel density were compared between Plg+/+ and Plg-/- mice at different time points after stroke. We found that Plg-/- mice exhibited significantly reduced functional recovery, associated with significantly decreased vessel density in the peri-infarct area in the ipsilesional cortex compared with Plg+/+ mice. In vitro, cerebral endothelial cells harvested from Plg-/- mice exhibited significantly reduced angiogenesis assessed using tube formation assay, and migration, as evaluated using Scratch assays, compared to endothelial cells harvested from Plg+/+ mice. In addition, using Western blots, expression of thrombospondin (TSP)-1 and TSP-2 were increased after MCAo in the Plg-/- group compared to Plg+/+ mice, especially in the ipsilesional side of brain. Taken together, our data suggest that plasmin/plasminogen down-regulates the expression level of TSP-1 and TSP-2, and thereby promotes angiogenesis in the peri-ischemic brain tissue, which contributes to functional recovery after ischemic stroke.



J Cereb Blood Flow Metab: 13 Apr 2021:271678X211007958; epub ahead of print
Fang J, Chopp M, Xin H, Zhang L, ... He L, Liu Z
J Cereb Blood Flow Metab: 13 Apr 2021:271678X211007958; epub ahead of print | PMID: 33853408
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Impact:
Abstract

Much ado about eating: Intermittent fasting and post-stroke neuroprotection.

Vemuganti R, Arumugam TV
A proper diet is important for health and longevity. Controlling the amount of food consumed is immensely beneficial as it promotes multiple cellular and molecular protective mechanisms and simultaneously prevents toxic mechanisms. Intermittent fasting (IF) is a flexible and easy-to-adopt dietary modification that helps to mitigate metabolic disorders like diabetes and hypertension, and thus the devastating age-related diseases like heart attack, stroke and dementia. The benefits of IF seem to be mediated by altered epigenetic and transcriptional programming leading to reduced oxidative stress, inflammation, mitochondrial damage and cell death.



J Cereb Blood Flow Metab: 13 Apr 2021:271678X211009362; epub ahead of print
Vemuganti R, Arumugam TV
J Cereb Blood Flow Metab: 13 Apr 2021:271678X211009362; epub ahead of print | PMID: 33853407
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Abstract

Role of endothelium-pericyte signaling in capillary blood flow response to neuronal activity.

Zhang W, Davis CM, Zeppenfeld DM, Golgotiu K, ... Iliff JJ, Alkayed NJ
Local blood flow in the brain is tightly coupled to metabolic demands, a phenomenon termed functional hyperemia. Both capillaries and arterioles contribute to the hyperemic response to neuronal activity via different mechanisms and timescales. The nature and specific signaling involved in the hyperemic response of capillaries versus arterioles, and their temporal relationship are not fully defined. We determined the time-dependent changes in capillary flux and diameter versus arteriolar velocity and flow following whisker stimulation using optical microangiography (OMAG) and two-photon microscopy. We further characterized depth-resolved responses of individual capillaries versus capillary networks. We hypothesized that capillaries respond first to neuronal activation, and that they exhibit a coordinated response mediated via endothelial-derived epoxyeicosatrienoates (EETs) acting on pericytes. To visualize peri-capillary pericytes, we used Tie2-GFP/NG2-DsRed mice, and to determine the role of endothelial-derived EETs, we compared cerebrovascular responses to whisker stimulation between wild-type mice and mice with lower endothelial EETs (Tie2-hsEH). We found that capillaries respond immediately to neuronal activation in an orchestrated network-level manner, a response attenuated in Tie2-hsEH and inhibited by blocking EETs action on pericytes. These results demonstrate that capillaries are first responders during functional hyperemia, and that they exhibit a network-level response mediated via endothelial-derived EETs\' action on peri-capillary pericytes.



J Cereb Blood Flow Metab: 13 Apr 2021:271678X211007957; epub ahead of print
Zhang W, Davis CM, Zeppenfeld DM, Golgotiu K, ... Iliff JJ, Alkayed NJ
J Cereb Blood Flow Metab: 13 Apr 2021:271678X211007957; epub ahead of print | PMID: 33853406
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Abstract

[C]deschloroclozapine is an improved PET radioligand for quantifying a human muscarinic DREADD expressed in monkey brain.

Yan X, Telu S, Dick RM, Liow JS, ... Richmond BJ, Eldridge MA
Previous work found that [11C]deschloroclozapine ([11C]DCZ) is superior to [11C]clozapine ([11C]CLZ) for imaging Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). This study used PET to quantitatively and separately measure the signal from transfected receptors, endogenous receptors/targets, and non-displaceable binding in other brain regions to better understand this superiority. A genetically-modified muscarinic type-4 human receptor (hM4Di) was injected into the right amygdala of a male rhesus macaque. [11C]DCZ and [11C]CLZ PET scans were conducted 2-24 months later. Uptake was quantified relative to the concentration of parent radioligand in arterial plasma at baseline (n = 3 scans/radioligand) and after receptor blockade (n = 3 scans/radioligand). Both radioligands had greater uptake in the transfected region and displaceable uptake in other brain regions. Displaceable uptake was not uniformly distributed, perhaps representing off-target binding to endogenous receptor(s). After correction, [11C]DCZ signal was 19% of that for [11C]CLZ, and background uptake was 10% of that for [11C]CLZ. Despite stronger [11C]CLZ binding, the signal-to-background ratio for [11C]DCZ was almost two-fold greater than for [11C]CLZ. Both radioligands had comparable DREADD selectivity. All reference tissue models underestimated signal-to-background ratio in the transfected region by 40%-50% for both radioligands. Thus, the greater signal-to-background ratio of [11C]DCZ was due to its lower background uptake.



J Cereb Blood Flow Metab: 13 Apr 2021:271678X211007949; epub ahead of print
Yan X, Telu S, Dick RM, Liow JS, ... Richmond BJ, Eldridge MA
J Cereb Blood Flow Metab: 13 Apr 2021:271678X211007949; epub ahead of print | PMID: 33853405
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Abstract

Three-dimensional remodeling of functional cerebrovascular architecture and gliovascular unit in leptin receptor-deficient mice.

Liu Y, Chen D, Smith A, Ye Q, Gao Y, Zhang W
The cerebrovascular sequelae of diabetes render victims more susceptible to ischemic stroke, vascular cognitive impairment, and Alzheimer\'s disease. However, limited knowledge exists on the progressive changes in cerebrovascular structure and functional remodeling in type 2 diabetes. To ascertain the impact of diabetes on whole-brain cerebrovascular perfusion, leptin-receptor-deficient mice were transcardially injected with tomato-lectin before sacrifice. The whole brain was clarified by the Fast free-of-acrylamide clearing tissue technique. Functional vascular anatomy of the cerebrum was visualized by light-sheet microscopy, followed by analysis in Imaris software. We observed enhanced neovascularization in adult db/db mice, characterized by increased branch level and loop structures. Microvascular hypoperfusion was initially detected in juvenile db/db mice, suggesting early onset of insufficient microcirculation. Furthermore, gliovascular unit remodeling was verified by loss of pericytes and overactivation of microglia and astrocytes in adult diabetic mice. However, the integrity of the blood-brain barrier (BBB) was fundamentally preserved, as shown by a lack of extravasation of IgG into the brain parenchyma. In summary, we, for the first time, reveal that functional cerebrovascular remodeling occurs as early as four weeks in db/db mice and the deficit in gliovascular coupling may play a role in cerebral hypoperfusion before BBB breakdown in 16-week-old db/db mice.



J Cereb Blood Flow Metab: 03 Apr 2021:271678X211006596; epub ahead of print
Liu Y, Chen D, Smith A, Ye Q, Gao Y, Zhang W
J Cereb Blood Flow Metab: 03 Apr 2021:271678X211006596; epub ahead of print | PMID: 33818188
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Abstract

Cerebral critical closing pressure and resistance-area product: the influence of dynamic cerebral autoregulation, age, and sex.

Panerai RB, Haunton VJ, Llwyd O, Minhas JS, ... Maggio P, Robinson TG
Instantaneous arterial pressure-flow (or velocity) relationships indicate the existence of a cerebral critical closing pressure (CrCP), with the slope of the relationship expressed by the resistance-area product (RAP). In 194 healthy subjects (20-82 years, 90 female), cerebral blood flow velocity (CBFV, transcranial Doppler), arterial blood pressure (BP, Finapres) and end-tidal CO2 (EtCO2, capnography) were measured continuously for five minutes during spontaneous fluctuations of BP at rest. The dynamic cerebral autoregulation (CA) index (ARI) was extracted with transfer function analysis from the CBFV step response to the BP input and step responses were also obtained for the BP-CrCP and BP-RAP relationships. ARI was shown to decrease with age at a rate of -0.025 units/year in men (p = 0.022), but not in women (p = 0.40). The temporal patterns of the BP-CBFV, BP-CrCP and BP-RAP step responses were strongly influenced by the ARI (p < 0.0001), but not by sex. Age was also a significant determinant of the peak of the CBFV step response and the tail of the RAP response. Whilst the RAP step response pattern is consistent with a myogenic mechanism controlling dynamic CA, further work is needed to explore the potential association of the CrCP step response with the flow-mediated component of autoregulation.



J Cereb Blood Flow Metab: 03 Apr 2021:271678X211004131; epub ahead of print
Panerai RB, Haunton VJ, Llwyd O, Minhas JS, ... Maggio P, Robinson TG
J Cereb Blood Flow Metab: 03 Apr 2021:271678X211004131; epub ahead of print | PMID: 33818187
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Abstract

Dilated perivascular space is related to reduced free-water in surrounding white matter among healthy adults and elderlies but not in patients with severe cerebral small vessel disease.

Jiaerken Y, Lian C, Huang P, Yu X, ... Shen D, Zhang M
Perivascular space facilitates cerebral interstitial water clearance. However, it is unclear how dilated perivascular space (dPVS) affects the interstitial water of surrounding white matter. We aimed to determine the presence and extent of changes in normal-appearing white matter water components around dPVS in different populations. Twenty healthy elderly subjects and 15 elderly subjects with severe cerebral small vessel disease (CSVD, with lacunar infarction 6 months before the scan) were included in our study. And other 28 healthy adult subjects were enrolled under a different scanning parameter to see if the results are comparable. The normal-appearing white matter around dPVS was categorized into 10 layers (1 mm thickness each) based on their distance to dPVS. We evaluated the mean isotropic-diffusing water volume fraction in each layer. We discovered a significantly reduced free-water content in the layers closely adjacent to the dPVS in the healthy elderlies. however, this reduction around dPVS was weaker in the CSVD subjects. We also discovered an elevated free-water content within dPVS. DPVS played different roles in healthy subjects or CSVD subjects. The reduced water content around dPVS in healthy subjects suggests these MR-visible PVSs are not always related to the stagnation of fluid.



J Cereb Blood Flow Metab: 03 Apr 2021:271678X211005875; epub ahead of print
Jiaerken Y, Lian C, Huang P, Yu X, ... Shen D, Zhang M
J Cereb Blood Flow Metab: 03 Apr 2021:271678X211005875; epub ahead of print | PMID: 33818186
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Impact:
Abstract

A large portion of the astrocyte proteome is dedicated to perivascular endfeet, including critical components of the electron transport chain.

Stokum JA, Shim B, Huang W, Kane M, ... Gerzanich V, Simard JM
The perivascular astrocyte endfoot is a specialized and diffusion-limited subcellular compartment that fully ensheathes the cerebral vasculature. Despite their ubiquitous presence, a detailed understanding of endfoot physiology remains elusive, in part due to a limited understanding of the proteins that distinguish the endfoot from the greater astrocyte body. Here, we developed a technique to isolate astrocyte endfeet from brain tissue, which was used to study the endfoot proteome in comparison to the astrocyte somata. In our approach, brain microvessels, which retain their endfoot processes, were isolated from mouse brain and dissociated, whereupon endfeet were recovered using an antibody-based column astrocyte isolation kit. Our findings expand the known set of proteins enriched at the endfoot from 10 to 516, which comprised more than 1/5th of the entire detected astrocyte proteome. Numerous critical electron transport chain proteins were expressed only at the endfeet, while enzymes involved in glycogen storage were distributed to the somata, indicating subcellular metabolic compartmentalization. The endfoot proteome also included numerous proteins that, while known to have important contributions to blood-brain barrier function, were not previously known to localize to the endfoot. Our findings highlight the importance of the endfoot and suggest new routes of investigation into endfoot function.



J Cereb Blood Flow Metab: 03 Apr 2021:271678X211004182; epub ahead of print
Stokum JA, Shim B, Huang W, Kane M, ... Gerzanich V, Simard JM
J Cereb Blood Flow Metab: 03 Apr 2021:271678X211004182; epub ahead of print | PMID: 33818185
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Abstract

Nicotinamide phosphoribosyltransferase inhibitor ameliorates mouse aging-induced cognitive impairment.

Zeng M, Wei TF, Chen C, Shen C, ... Lu YB, Zhang WP
Nicotinamide phosphoribosyltransferase (NAMPT) is the key enzyme for the synthesis of nicotinamide adenine dinucleotide (NAD) in the salvaging pathway. Though NAMPT inhibitors such as FK866 were originally developed as anti-cancer drugs, they also display neuroprotective effects. Here we show that the administration of FK866 at 0.5 mg/kg (ip, qod) for four weeks, i.e., ∼1% of the dose used for the treatment of cancer, significantly alleviates the aging-induced impairment of cognition and locomotor activity. Mechanistically, FK866 enhanced autophagy, reduced protein aggregation, and inhibited neuroinflammation indicated by decreasing TNFα, IL-6, GFAP, and Iba1 levels in the aged mouse brain. Though FK866 did not affect the total NAD and nicotinamide mononucleotide (NMN) levels in the mouse brain at the dose we used, FK866 increased nicotinamide (NAM) level in the young mouse brain and decreased NAM level in the aged mouse brain. On the other hand, FK866 did not affect the serum glucose, cholesterol, and triglyceride of young and aged mice and exhibited no effects on the various indices of young mice. Thus, the NAMPT inhibitor can be repurpose to counteract the cognitive impairment upon aging. We also envision that NAMPT inhibitor can be used for the treatment of age-related neurodegenerative diseases.



J Cereb Blood Flow Metab: 03 Apr 2021:271678X211006291; epub ahead of print
Zeng M, Wei TF, Chen C, Shen C, ... Lu YB, Zhang WP
J Cereb Blood Flow Metab: 03 Apr 2021:271678X211006291; epub ahead of print | PMID: 33818184
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Abstract

Neurochemical underpinning of hemodynamic response to neuropsychiatric drugs: A meta- and cluster analysis of preclinical studies.

Mervin LH, Mitricheva E, Logothetis NK, Bifone A, Bender A, Noori HR
Functional magnetic resonance imaging (fMRI) is an extensively used method for the investigation of normal and pathological brain function. In particular, fMRI has been used to characterize spatiotemporal hemodynamic response to pharmacological challenges as a non-invasive readout of neuronal activity. However, the mechanisms underlying regional signal changes are yet unclear. In this study, we use a meta-analytic approach to converge data from microdialysis experiments with relative cerebral blood volume (rCBV) changes following acute administration of neuropsychiatric drugs in adult male rats. At whole-brain level, the functional response patterns show very weak correlation with neurochemical alterations, while for numerous brain areas a strong positive correlation with noradrenaline release exists. At a local scale of individual brain regions, the rCBV response to neurotransmitters is anatomically heterogeneous and, importantly, based on a complex interplay of different neurotransmitters that often exert opposing effects, thus providing a mechanism for regulating and fine tuning hemodynamic responses in specific regions.



J Cereb Blood Flow Metab: 30 Mar 2021; 41:874-885
Mervin LH, Mitricheva E, Logothetis NK, Bifone A, Bender A, Noori HR
J Cereb Blood Flow Metab: 30 Mar 2021; 41:874-885 | PMID: 32281457
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Abstract

A non-human primate model of stroke reproducing endovascular thrombectomy and allowing long-term imaging and neurological read-outs.

Debatisse J, Wateau O, Cho TH, Costes N, ... Canet-Soulas E, Eker OF
Stroke is a devastating disease. Endovascular mechanical thrombectomy is dramatically changing the management of acute ischemic stroke, raising new challenges regarding brain outcome and opening up new avenues for brain protection. In this context, relevant experiment models are required for testing new therapies and addressing important questions about infarct progression despite successful recanalization, reversibility of ischemic lesions, blood-brain barrier disruption and reperfusion damage. Here, we developed a minimally invasive non-human primate model of cerebral ischemia (Macaca fascicularis) based on an endovascular transient occlusion and recanalization of the middle cerebral artery (MCA). We evaluated per-occlusion and post-recanalization impairment on PET-MRI, in addition to acute and chronic neuro-functional assessment. Voxel-based analyses between per-occlusion PET-MRI and day-7 MRI showed two different patterns of lesion evolution: \"symptomatic salvaged tissue\" (SST) and \"asymptomatic infarcted tissue\" (AIT). Extended SST was present in all cases. AIT, remote from the area at risk, represented 45% of the final lesion. This model also expresses both worsening of fine motor skills and dysexecutive behavior over the chronic post-stroke period, a result in agreement with cortical-subcortical lesions. We thus fully characterized an original translational model of ischemia-reperfusion damage after stroke, with consistent ischemia time, and thrombus retrieval for effective recanalization.



J Cereb Blood Flow Metab: 30 Mar 2021; 41:745-760
Debatisse J, Wateau O, Cho TH, Costes N, ... Canet-Soulas E, Eker OF
J Cereb Blood Flow Metab: 30 Mar 2021; 41:745-760 | PMID: 32428423
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Impact:
Abstract

Test-retest variability and reference region-based quantification of F-BCPP-EF for imaging mitochondrial complex I in the human brain.

Mansur A, Rabiner EA, Tsukada H, Comley RA, ... Passchier J, Gunn RN
Mitochondrial complex I (MC-I) is an essential regulator of brain bioenergetics and can be quantified in the brain using PET radioligand 18F-BCPP-EF. Here we evaluate the test-retest reproducibility of 18F-BCPP-EF in humans, and assess the use of a non-invasive quantification method (standardised uptake value ratio - SUVR). Thirty healthy volunteers had a 90-min dynamic 18F-BCPP-EF scan with arterial blood sampling, five of which received a second scan to be included in the test-retest analysis. Time-activity curves (TAC) were analysed using multilinear analysis 1 (MA1) and the two-tissue compartment model (2TC) to estimate volumes of distribution (VT). Regional SUVR-1 values were calculated from the 70 to 90-min TAC data using the centrum semiovale as a pseudo reference region, and compared to kinetic analysis-derived outcome measures. The mean absolute test-retest variability of VT ranged from 12% to 18% across regions. Both DVR-1and SUVR-1 had improved test-retest variability in the range 2%-7%. SUVR-1 was highly correlated with DVR-1 (r2 = 0.97, n = 30). In conclusion, 18F-BCPP-EF has suitable test-retest reproducibility and can be used to quantify MC-I in clinical studies.



J Cereb Blood Flow Metab: 30 Mar 2021; 41:771-779
Mansur A, Rabiner EA, Tsukada H, Comley RA, ... Passchier J, Gunn RN
J Cereb Blood Flow Metab: 30 Mar 2021; 41:771-779 | PMID: 32501157
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Abstract

Mitochondrial transfer from mesenchymal stem cells improves neuronal metabolism after oxidant injury in vitro: The role of Miro1.

Tseng N, Lambie SC, Huynh CQ, Sanford B, ... Herson PS, Ormond DR
Stroke-induced cerebral ischemia is a major cause of death and disability. The disruption of blood flow results in neuronal and glial cell death leading to brain injury. Reperfusion restores oxygen to the affected tissue, but can also cause damage through an enhanced oxidative stress and inflammatory response. This study examines mitochondrial transfer from MSC to neurons and the role it plays in neuronal preservation after oxidant injury. We observed the transfer of mitochondria from MSC to mouse neurons in vitro following hydrogen peroxide exposure. The observed transfer was dependent on cell-to-cell contact and led to increased neuronal survival and improved metabolism. A number of pro-inflammatory and mitochondrial motility genes were upregulated in neurons after hydrogen peroxide exposure. This included Miro1 and TNFAIP2, linking inflammation and mitochondrial transfer to oxidant injury. Increasing Miro1 expression in MSC improved the metabolic benefit of mitochondrial transfer after neuronal oxidant injury. Decreasing Miro1 expression had the opposite effect, decreasing the metabolic benefit of MSC co-culture. MSC transfer of mitochondria to oxidant-damaged neurons may help improve neuronal preservation and functional recovery after stroke.



J Cereb Blood Flow Metab: 30 Mar 2021; 41:761-770
Tseng N, Lambie SC, Huynh CQ, Sanford B, ... Herson PS, Ormond DR
J Cereb Blood Flow Metab: 30 Mar 2021; 41:761-770 | PMID: 32501156
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Abstract

Cerebral metabolic rate of oxygen during transition from wakefulness to sleep measured with high temporal resolution OxFlow MRI with concurrent EEG.

Caporale A, Lee H, Lei H, Rao H, ... Wu PH, Wehrli FW
During slow-wave sleep, synaptic transmissions are reduced with a concomitant reduction in brain energy consumption. We used 3 Tesla MRI to noninvasively quantify changes in the cerebral metabolic rate of O2 (CMRO2) during wakefulness and sleep, leveraging the \'OxFlow\' method, which provides venous O2 saturation (SvO2) along with cerebral blood flow (CBF). Twelve healthy subjects (31.3 ± 5.6 years, eight males) underwent 45-60 min of continuous scanning during wakefulness and sleep, yielding one image set every 3.4 s. Concurrent electroencephalography (EEG) data were available in eight subjects. Mean values of the metabolic parameters measured during wakefulness were stable, with coefficients of variation below 7% (average values: CMRO2 = 118 ± 12 µmol O2/min/100 g, SvO2 = 67.0 ± 3.7% HbO2, CBF = 50.6 ±4.3 ml/min/100 g). During sleep, on average, CMRO2 decreased 21% (range: 14%-32%; average nadir = 98 ± 16 µmol O2/min/100 g), while EEG slow-wave activity, expressed in terms of δ -power, increased commensurately. Following sleep onset, CMRO2 was found to correlate negatively with relative δ -power (r = -0.6 to -0.8, P < 0.005), and positively with heart rate (r = 0.5 to 0.8, P < 0.0005). The data demonstrate that OxFlow MRI can noninvasively measure dynamic changes in cerebral metabolism associated with sleep, which should open new opportunities to study sleep physiology in health and disease.



J Cereb Blood Flow Metab: 30 Mar 2021; 41:780-792
Caporale A, Lee H, Lei H, Rao H, ... Wu PH, Wehrli FW
J Cereb Blood Flow Metab: 30 Mar 2021; 41:780-792 | PMID: 32538283
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Abstract

Reversal of neurovascular coupling in the default mode network: Evidence from hypoxia.

Rossetti GM, d\'Avossa G, Rogan M, Macdonald JH, Oliver SJ, Mullins PG
Local changes in cerebral blood flow are thought to match changes in neuronal activity, a phenomenon termed neurovascular coupling. Hypoxia increases global resting cerebral blood flow, but regional cerebral blood flow (rCBF) changes are non-uniform. Hypoxia decreases baseline rCBF to the default mode network (DMN), which could reflect either decreased neuronal activity or altered neurovascular coupling. To distinguish between these hypotheses, we characterized the effects of hypoxia on baseline rCBF, task performance, and the hemodynamic (BOLD) response to task activity. During hypoxia, baseline CBF increased across most of the brain, but decreased in DMN regions. Performance on memory recall and motion detection tasks was not diminished, suggesting task-relevant neuronal activity was unaffected. Hypoxia reversed both positive and negative task-evoked BOLD responses in the DMN, suggesting hypoxia reverses neurovascular coupling in the DMN of healthy adults. The reversal of the BOLD response was specific to the DMN. Hypoxia produced modest increases in activations in the visual attention network (VAN) during the motion detection task, and had no effect on activations in the visual cortex during visual stimulation. This regional specificity may be particularly pertinent to clinical populations characterized by hypoxemia and may enhance understanding of regional specificity in neurodegenerative disease pathology.



J Cereb Blood Flow Metab: 30 Mar 2021; 41:805-818
Rossetti GM, d'Avossa G, Rogan M, Macdonald JH, Oliver SJ, Mullins PG
J Cereb Blood Flow Metab: 30 Mar 2021; 41:805-818 | PMID: 32538282
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Abstract

Simultaneous nicotine and oral contraceptive exposure alters brain energy metabolism and exacerbates ischemic stroke injury in female rats.

Diaz F, Raval AP
Smoking-derived nicotine (N) and oral contraceptives (OC) synergistically exacerbate ischemic brain damage in the females and underlying mechanisms remain elusive. Our published study showed that N toxicity is exacerbated by OC via altered mitochondrial function owing to a defect in the activity of cytochrome c oxidase. Here, we investigated the global metabolomic profile of brains of adolescent female Sprague-Dawley rats exposed to N ± OC. Rats were randomly exposed to saline or N + /-OC for 16-21 days followed by random allocation into two cohorts. One cohort underwent transient middle cerebral artery occlusion and histopathology was performed 30 days later. From the second cohort, cortical tissues were collected for an unbiased global metabolomic profile. Pathway enrichment analysis showed significant decrease in glucose, glucose 6-phosphate and fructose-6-phosphate, along with a significant increase in pyruvate in the N + /-OC exposed groups when compared to saline (p < 0.05), suggesting alterations in the glycolytic pathway which were confirmed by Western blot analyses of glycolytic enzymes. Infarct volume quantification showed a significant increase following N alone or N + OC as compared to saline control. Because glucose metabolism is critical for brain physiology, altered glycolysis deteriorates neural function, thus exacerbating ischemic brain damage.



J Cereb Blood Flow Metab: 30 Mar 2021; 41:793-804
Diaz F, Raval AP
J Cereb Blood Flow Metab: 30 Mar 2021; 41:793-804 | PMID: 32538281
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Impact:
Abstract

In vivo imaging of synaptic SV2A protein density in healthy and striatal-lesioned rats with [11C]UCB-J PET.

Thomsen MB, Jacobsen J, Lillethorup TP, Schacht AC, ... Brooks DJ, Landau AM
The number of functionally active synapses provides a measure of neural integrity, with reductions observed in neurodegenerative disorders. [11C]UCB-J binds to synaptic vesicle 2A (SV2A) transmembrane protein located in secretory vesicles. We aimed to assess [11C]UCB-J PET as an in vivo biomarker of regional cerebral synaptic SV2A density in rat lesion models of neurodegeneration. Healthy anesthetized rats had [11C]UCB-J PET and arterial blood sampling. We compared different models describing [11C]UCB-J brain uptake kinetics to determine its regional distribution. Blocking studies were performed with levetiracetam (LEV), an antiepileptic SV2A antagonist. Tracer binding was measured in rodent unilateral acute lesion models of Parkinsonism and Huntington\'s disease, induced with 6-hydroxydopamine (6-OHDA) and quinolinic acid (QA), respectively. [3H]UCB-J autoradiography was performed in postmortem tissue. Rat brain showed high and fast [11C]UCB-J uptake and washout with up to 80% blockade by LEV. [11C]UCB-J PET showed a 6.2% decrease in ipsilateral striatal SV2A binding after 6-OHDA and 39.3% and 55.1% decreases after moderate and high dose QA confirmed by autoradiography. In conclusion, [11C]UCB-J PET provides a good in vivo marker of synaptic SV2A density which can potentially be followed longitudinally along with synaptic responses to putative neuroprotective agents in models of neurodegeneration.



J Cereb Blood Flow Metab: 30 Mar 2021; 41:819-830
Thomsen MB, Jacobsen J, Lillethorup TP, Schacht AC, ... Brooks DJ, Landau AM
J Cereb Blood Flow Metab: 30 Mar 2021; 41:819-830 | PMID: 32538280
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Impact:
Abstract

Cerebral perfusion is associated with blast exposure in military personnel without moderate or severe TBI.

Sullivan DR, Miller MW, Wolf EJ, Logue MW, ... McGlinchey RE, Salat DH
Due to the use of improvised explosive devices, blast exposure and mild traumatic brain injury (mTBI) have become hallmark injuries of the Iraq and Afghanistan wars. Although the mechanisms of the effects of blast on human neurobiology remain active areas of investigation, research suggests that the cerebrovasculature may be particularly vulnerable to blast via molecular processes that impact cerebral blood flow. Given that recent work suggests that blast exposure, even without a subsequent TBI, may have negative consequences on brain structure and function, the current study sought to further understand the effects of blast exposure on perfusion. One hundred and eighty military personnel underwent pseudo-continuous arterial spin labeling (pCASL) imaging and completed diagnostic and clinical interviews. Whole-brain analyses revealed that with an increasing number of total blast exposures, there was significantly increased perfusion in the right middle/superior frontal gyri, supramarginal gyrus, lateral occipital cortex, and posterior cingulate cortex as well as bilateral anterior cingulate cortex, insulae, middle/superior temporal gyri and occipital poles. Examination of other neurotrauma and clinical variables such as close-range blast exposures, mTBI, and PTSD yielded no significant effects. These results raise the possibility that perfusion may be an important neural marker of brain health in blast exposure.



J Cereb Blood Flow Metab: 30 Mar 2021; 41:886-900
Sullivan DR, Miller MW, Wolf EJ, Logue MW, ... McGlinchey RE, Salat DH
J Cereb Blood Flow Metab: 30 Mar 2021; 41:886-900 | PMID: 32580671
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Impact:
Abstract

Altered coupling of cerebral blood flow and functional connectivity strength in visual and higher order cognitive cortices in primary open angle glaucoma.

Wang Q, Qu X, Chen W, Wang H, ... Wang N, Xian J
Primary open-angle glaucoma (POAG) has been suggested to be a neurodegenerative disease associated with altered cerebral vascular hemodynamics and widespread disruption of neuronal activity within the visual, working memory, attention and executive networks. We hypothesized that disturbed neurovascular coupling in visual and higher order cognitive cortices exists in POAG patients and correlates with glaucoma stage and visual field defects. Through multimodal magnetic resonance imaging, we evaluated the cerebral blood flow (CBF)-functional connectivity strength (FCS) correlations of the whole gray matter and CBF/FCS ratio per voxel for all subjects. Compared with normal controls, POAG patients showed reduced global CBF-FCS coupling and altered CBF/FCS ratios, predominantly in regions in the visual cortex, salience network, default mode network, and dorsal attentional network. The CBF/FCS ratio was negatively correlated with glaucoma stage, and positively correlated with visual field defects in the lingual gyrus in POAG patients. Moreover, early brain changes were detected in early POAG. These findings indicate neurovascular coupling dysfunction might exist in the visual and higher order cognitive cortices in POAG patients and its clinical relevance. The results may contribute to the monitoring of POAG progression and provide insight into the pathophysiology of the neurodegenerative process in POAG.



J Cereb Blood Flow Metab: 30 Mar 2021; 41:901-913
Wang Q, Qu X, Chen W, Wang H, ... Wang N, Xian J
J Cereb Blood Flow Metab: 30 Mar 2021; 41:901-913 | PMID: 32580669
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Impact:
Abstract

Intranasal salvinorin A improves neurological outcome in rhesus monkey ischemic stroke model using autologous blood clot.

Wu L, Wu D, Chen J, Chen C, ... Liu R, Ji X
Salvinorin A (SA) exerts neuroprotection and improves neurological outcomes in ischemic stroke models in rodents. In this study, we investigated whether intranasal SA administration could improve neurological outcomes in a monkey ischemic stroke model. The stroke model was induced in adult male rhesus monkeys by occluding the middle cerebral artery M2 segment with an autologous blood clot. Eight adult rhesus monkeys were randomly administered SA or 10% dimethyl sulfoxide as control 20 min after ischemia. Magnetic resonance imaging was used to confirm the ischemia and extent of injury. Neurological function was evaluated using the Non-Human Primate Stroke Scale (NHPSS) over a 28-day observation period. SA significantly reduced infarct volume (3.9 ± 0.7 cm3 vs. 7.2 ± 1.0 cm3; P =0.002), occupying effect (0.3 ± 0.2% vs. 1.4 ± 0.3%; P =0.002), and diffusion limitation in the lesion (-28.2 ± 11.0% vs. -51.5 ± 7.1%; P =0.012) when compared to the control group. SA significantly reduced the NHPSS scores to almost normal in a 28-day observation period as compared to the control group (P =0.005). Intranasal SA reduces infarct volume and improves neurological outcomes in a rhesus monkey ischemic stroke model using autologous blood clot.



J Cereb Blood Flow Metab: 30 Mar 2021; 41:723-730
Wu L, Wu D, Chen J, Chen C, ... Liu R, Ji X
J Cereb Blood Flow Metab: 30 Mar 2021; 41:723-730 | PMID: 32615886
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Impact:
Abstract

High-altitude rodents have abundant collaterals that protect against tissue injury after cerebral, coronary and peripheral artery occlusion.

Faber JE, Storz JF, Cheviron ZA, Zhang H
Collateral number/density varies widely in brain and other tissues among strains of Mus musculus mice due to differences in genetic background. Recent studies have shown that prolonged exposure to reduced atmospheric oxygen induces additional collaterals to form, suggesting that natural selection may favor increased collaterals in populations native to high-altitude. High-altitude guinea pigs (Cavia) and deer mice (Peromyscus) were compared with lowland species of Peromyscus, Mus and Rattus (9 species/strains examined). Collateral density, diameter and other morphometrics were measured in brain where, importantly, collateral abundance reflects that in other tissues of the same individual. Guinea pigs and high-altitude deer mice had a greater density of pial collaterals than lowlanders. Consistent with this, guinea pigs and highlander mice evidenced complete and 80% protection against stroke, respectively. They also sustained significantly less ischemia in heart and lower extremities after arterial occlusion. Vessels of the circle of Willis, including the communicating collateral arteries, also exhibited unique features in the highland species. Our findings support the hypothesis that species native to high-altitude have undergone genetic selection for abundant collaterals, suggesting that besides providing protection in obstructive disease, collaterals serve a physiological function to optimize oxygen delivery to meet oxygen demand when oxygen is limiting.



J Cereb Blood Flow Metab: 30 Mar 2021; 41:731-744
Faber JE, Storz JF, Cheviron ZA, Zhang H
J Cereb Blood Flow Metab: 30 Mar 2021; 41:731-744 | PMID: 32703056
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Impact:
Abstract

Cerebrovascular and neurological perspectives on adrenoceptor and calcium channel modulating pharmacotherapies.

Gezalian MM, Mangiacotti L, Rajput P, Sparrow N, Schlick K, Lahiri S
Adrenoceptor and calcium channel modulating medications are widely used in clinical practice for acute neurological and systemic conditions. It is generally assumed that the cerebrovascular effects of these drugs mirror that of their systemic effects - and this is reflected in how these medications are currently used in clinical practice. However, recent research suggests that there are distinct cerebrovascular-specific effects of these medications that are related to the unique characteristics of the cerebrovascular anatomy including the regional heterogeneity in density and distribution of adrenoceptor subtypes and calcium channels along the cerebrovasculature. In this review, we critically evaluate existing basic science and clinical research to discuss known and putative interactions between adrenoceptor and calcium channel modulating pharmacotherapies, the neurovascular unit, and cerebrovascular anatomy. In doing so, we provide a rationale for selecting vasoactive medications based on lesion location and lay a foundation for future investigations that will define neuroprotective paradigms of adrenoceptor and calcium channel modulating therapies to improve neurological outcomes in acute neurological and systemic disorders.



J Cereb Blood Flow Metab: 30 Mar 2021; 41:693-706
Gezalian MM, Mangiacotti L, Rajput P, Sparrow N, Schlick K, Lahiri S
J Cereb Blood Flow Metab: 30 Mar 2021; 41:693-706 | PMID: 33210576
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Impact:
Abstract

Effect of uric acid in animal models of ischemic stroke: A systematic review and meta-analysis.

Aliena-Valero A, Baixauli-Martín J, Castelló-Ruiz M, Torregrosa G, Hervás D, Salom JB
Addition of uric acid (UA) to thrombolytic therapy, although safe, showed limited efficacy in improving patients\' stroke outcome, despite alleged neuroprotective effects of UA in preclinical research. This systematic review assessed the effects of UA on brain structural and functional outcomes in animal models of ischemic stroke. We searched Medline, Embase and Web of Science to identify 16 and 14 eligible rodent studies for qualitative and quantitative synthesis, respectively. Range of evidence met 10 of a possible 13 STAIR criteria. Median (Q1, Q3) quality score was 7.5 (6, 10) on the CAMARADES 15-item checklist. For each outcome, we used standardised mean difference (SMD) as effect size and random-effects modelling. Meta-analysis showed that UA significantly reduced infarct size (SMD: -1.18; 95% CI [-1.47, -0.88]; p < 0.001), blood-brain barrier (BBB) impairment/oedema (SMD: -0.72; 95% CI [-0.97, -0.48]; p < 0.001) and neurofunctional deficit (SMD: -0.98; 95% CI [-1.32, -0.63]; p < 0.001). Overall, there was low to moderate between-study heterogeneity and sizeable publication bias. In conclusion, published rodent data suggest that UA improves outcome following ischemic stroke by reducing infarct size, improving BBB integrity and ameliorating neurofunctional condition. Specific recommendations are given for further high-quality preclinical research required to better inform clinical research.



J Cereb Blood Flow Metab: 30 Mar 2021; 41:707-722
Aliena-Valero A, Baixauli-Martín J, Castelló-Ruiz M, Torregrosa G, Hervás D, Salom JB
J Cereb Blood Flow Metab: 30 Mar 2021; 41:707-722 | PMID: 33210575
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Abstract

Towards blood biomarkers for stroke patients.

Rust R
Stroke outcome considerably varies between stroke patients and often cannot be predicted. Now, Gendrun and colleagues investigated the suitability of blood neurofilament light chain proteins (NFL) as a biomarker of neuronal damage. High NFL levels correlated with brain injury, functional outcome and mortality following all major types of stroke. These data raise hope to revolutionize future prognosis and management of stroke patients.



J Cereb Blood Flow Metab: 30 Mar 2021; 41:914-916
Rust R
J Cereb Blood Flow Metab: 30 Mar 2021; 41:914-916 | PMID: 33563080
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Impact:
Abstract

Opposed hemodynamic responses following increased excitation and parvalbumin-based inhibition.

Lee J, Stile CL, Bice AR, Rosenthal ZP, ... Lee JM, Bauer AQ
Understanding cellular contributions to hemodynamic activity is essential for interpreting blood-based brain mapping signals. Optogenetic studies examining cell-specific influences on local hemodynamics have reported that excitatory activity results in cerebral perfusion and blood volume increase, while inhibitory activity contributes to both vasodilation and vasoconstriction. How specific subpopulations of interneurons regulate the brain\'s blood supply is less examined. Parvalbumin interneurons are the largest subpopulation of GABAergic neurons in the brain, critical for brain development, plasticity, and long-distance excitatory neurotransmission. Despite their essential role in brain function, the contribution of parvalbumin neurons to neurovascular coupling has been relatively unexamined. Using optical intrinsic signal imaging and laser speckle contrast imaging, we photostimulated awake and anesthetized transgenic mice expressing channelrhodopsin under a parvalbumin promoter. Increased parvalbumin activity reduced local oxygenation, cerebral blood volume, and cerebral blood flow. These \"negative\" hemodynamic responses were consistent within and across mice and reproducible across a broad range of photostimulus parameters. However, the sign and magnitude of the hemodynamic response resulting from increased parvalbumin activity depended on the type and level of anesthesia used. Opposed hemodynamic responses following increased excitation or parvalbumin-based inhibition suggest unique contributions from different cell populations to neurovascular coupling.



J Cereb Blood Flow Metab: 30 Mar 2021; 41:841-856
Lee J, Stile CL, Bice AR, Rosenthal ZP, ... Lee JM, Bauer AQ
J Cereb Blood Flow Metab: 30 Mar 2021; 41:841-856 | PMID: 33736512
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Impact:
Abstract

Galectin-3 protects against ischemic stroke by promoting neuro-angiogenesis via apoptosis inhibition and Akt/Caspase regulation.

Wesley UV, Sutton IC, Cunningham K, Jaeger JW, ... Hatcher JF, Dempsey RJ
Post-stroke neurological deficits and mortality are often associated with vascular disruption and neuronal apoptosis. Galectin-3 (Gal3) is a potent pro-survival and angiogenic factor. However, little is known about its protective role in the cerebral ischemia/reperfusion (I/R) injury. We have previously shown significant up-regulation of Gal3 in the post-stroke rat brain, and that blocking of Gal3 with neutralizing antibody decreases the cerebral blood vessel density. Our current study demonstrates that intracerebral local delivery of the Gal3 into rat brain at the time of reperfusion exerts neuroprotection. Ischemic lesion volume and neuronal cell death were significantly reduced as compared with the vehicle-treated MCAO rat brains. Gal3 increased vessel density and neuronal survival after I/R in rat brains. Importantly, Gal3-treated groups showed significant improvement in motor and sensory functional recovery. Gal3 increased neuronal cell viability under in vitro oxygen-glucose deprivation conditions in association with increased phosphorylated-Akt, decreased phosphorylated-ERK1/2, and reduced caspase-3 activity. Gene expression analysis showed down regulation of pro-apoptotic and inflammatory genes including Fas-ligand, and upregulation of pro-survival and pro-angiogenic genes including Bcl-2, PECAM, and occludin. These results indicate a key role for Gal3 in neuro-vascular protection and functional recovery following ischemic stroke through modulation of angiogenic and apoptotic pathways.



J Cereb Blood Flow Metab: 30 Mar 2021; 41:857-873
Wesley UV, Sutton IC, Cunningham K, Jaeger JW, ... Hatcher JF, Dempsey RJ
J Cereb Blood Flow Metab: 30 Mar 2021; 41:857-873 | PMID: 33736511
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Impact:
Abstract

Cerebrovascular reactivity in retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations.

Hoogeveen ES, Pelzer N, Ghariq E, van Osch MJ, ... Terwindt GM, Kruit MC
Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic manifestations (RVCL-S) is a small vessel disease caused by TREX1 mutations. RVCL-S is characterized by retinal vasculopathy and brain white matter lesions with and without contrast enhancement. We aimed to investigate cerebrovascular reactivity (CVR) in RVCL-S. In this cross-sectional observational study, 21 RVCL-S patients, 23 mutation-negative family members, and 31 healthy unrelated controls were included. CVR to a hypercapnic challenge was measured using dual-echo arterial spin labeling magnetic resonance imaging. Stratified analyses based on age were performed. We found that CVR was decreased in gray and white matter of RVCL-S patients compared with family members and healthy controls (ANCOVA; P < 0.05 for all comparisons). This was most noticeable in RVCL-S patients aged ≥40 years (ANCOVA, P < 0.05 for all comparisons). In RVCL-S patients aged < 40 years, only CVR in white matter was lower when compared to healthy controls (P < 0.05). Gray matter CVR was associated with white matter lesion volume in RVCL-S patients (r = -0.527, P = 0.01). In conclusion, impaired cerebrovascular reactivity may play an important role in the pathophysiology of RVCL-S and may be an useful early biomarker of cerebrovascular disease severity.



J Cereb Blood Flow Metab: 30 Mar 2021; 41:831-840
Hoogeveen ES, Pelzer N, Ghariq E, van Osch MJ, ... Terwindt GM, Kruit MC
J Cereb Blood Flow Metab: 30 Mar 2021; 41:831-840 | PMID: 33736510
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Impact:
Abstract

More than motor impairment: A spatiotemporal analysis of cognitive impairment and associated neuropathological changes following cortical photothrombotic stroke.

Sanchez-Bezanilla S, Hood RJ, Collins-Praino LE, Turner RJ, ... Nilsson M, Ong LK
There is emerging evidence suggesting that a cortical stroke can cause delayed and remote hippocampal dysregulation, leading to cognitive impairment. In this study, we aimed to investigate motor and cognitive outcomes after experimental stroke, and their association with secondary neurodegenerative processes. Specifically, we used a photothrombotic stroke model targeting the motor and somatosensory cortices of mice. Motor function was assessed using the cylinder and grid walk tasks. Changes in cognition were assessed using a mouse touchscreen platform. Neuronal loss, gliosis and amyloid-β accumulation were investigated in the peri-infarct and ipsilateral hippocampal regions at 7, 28 and 84 days post-stroke. Our findings showed persistent impairment in cognitive function post-stroke, whilst there was a modest spontaneous motor recovery over the investigated period of 84 days. In the peri-infarct region, we detected a reduction in neuronal loss and decreased neuroinflammation over time post-stroke, which potentially explains the spontaneous motor recovery. Conversely, we observed persistent neuronal loss together with concomitant increased neuroinflammation and amyloid-β accumulation in the hippocampus, which likely accounts for the persistent cognitive dysfunction. Our findings indicate that cortical stroke induces secondary neurodegenerative processes in the hippocampus, a region remote from the primary infarct, potentially contributing to the progression of post-stroke cognitive impairment.



J Cereb Blood Flow Metab: 27 Mar 2021:271678X211005877; epub ahead of print
Sanchez-Bezanilla S, Hood RJ, Collins-Praino LE, Turner RJ, ... Nilsson M, Ong LK
J Cereb Blood Flow Metab: 27 Mar 2021:271678X211005877; epub ahead of print | PMID: 33779358
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Impact:
Abstract

Review of major trials of acute blood pressure management in stroke.

Robinson TG, Minhas JS, Miller J
Over the last two decades, there have been a number of major landmark clinical trials, classified as \"major\" as they sought to address clear clinical practice driven questions, in a pragmatic yet robust trial design, using a large powered sample size (n > 1000), in order to help improve patient outcome through informing guidelines. A commonality across all stroke sub-types included in these trials is the tendency to acute hypertensive crises within the acute stroke period. This phenomenon is associated with greater stroke complications and worsened overall prognosis. Multiple trials have attempted to address the issue of acute blood pressure management during the acute stroke period, with consideration for timing, magnitude of lowering, agent and relationship to other interventions. This review will consider the major clinical trials performed in ischaemic and haemorrhagic stroke that test the hypothesis that acute BP reduction improves clinical outcomes.



J Cereb Blood Flow Metab: 23 Mar 2021:271678X211004310; epub ahead of print
Robinson TG, Minhas JS, Miller J
J Cereb Blood Flow Metab: 23 Mar 2021:271678X211004310; epub ahead of print | PMID: 33761781
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Impact:
Abstract

PET imaging of colony-stimulating factor 1 receptor: A head-to-head comparison of a novel radioligand, C-GW2580, and C-CPPC, in mouse models of acute and chronic neuroinflammation and a rhesus monkey.

Zhou X, Ji B, Seki C, Nagai Y, ... Kimura Y, Higuchi M
Colony-stimulating factor 1 receptor (CSF1R) is a specific biomarker for microglia. In this study, we developed a novel PET radioligand for CSF1R, 11C-GW2580, and compared it to a reported CSF1R tracer, 11C-CPPC, in mouse models of acute and chronic neuroinflammation and a rhesus monkey. Dynamic 11C-GW2580- and 11C-CPPC-PET images were quantified by reference tissue-based models and standardized uptake value ratio. Both tracers exhibited increased uptake in the lesioned striata of lipopolysaccharide-injected mice and in the forebrains of AppNL-G-F/NL-G-F-knock-in mice, spatially in agreement with an increased 18-kDa translocator protein radioligand retention. Moreover, 11C-GW2580 captured changes in CSF1R availability more sensitively than 11C-CPPC, with a larger dynamic range and a smaller inter-individual variability, in these model animals. PET imaging of CSF1R in a rhesus monkey displayed moderate-to-high tracer retention in the brain at baseline. Homologous blocker (i. e. unlabeled tracer) treatment reduced the uptake of 11C-GW2580 by ∼30% in all examined brain regions except for centrum semi-ovale white matter, but did not affect the retention of 11C-CPPC. In summary, our results demonstrated that 11C-GW2580-PET captured inflammatory microgliosis in the mouse brain with higher sensitivity than a reported radioligand, and displayed saturable binding in the monkey brain, potentially providing an imaging-based quantitative biomarker for reactive microgliosis.



J Cereb Blood Flow Metab: 23 Mar 2021:271678X211004146; epub ahead of print
Zhou X, Ji B, Seki C, Nagai Y, ... Kimura Y, Higuchi M
J Cereb Blood Flow Metab: 23 Mar 2021:271678X211004146; epub ahead of print | PMID: 33757319
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Impact:
Abstract

Comparison of [C]UCB-J and [F]FDG PET in Alzheimer\'s disease: A tracer kinetic modeling study.

Chen MK, Mecca AP, Naganawa M, Gallezot JD, ... van Dyck CH, Carson RE
[11C]UCB-J PET for synaptic vesicle glycoprotein 2 A (SV2A) has been proposed as a suitable marker for synaptic density in Alzheimer\'s disease (AD). We compared [11C]UCB-J binding for synaptic density and [18F]FDG uptake for metabolism (correlated with neuronal activity) in 14 AD and 11 cognitively normal (CN) participants. We assessed both absolute and relative outcome measures in brain regions of interest, i.e., K1 or R1 for [11C]UCB-J perfusion, VT (volume of distribution) or DVR to cerebellum for [11C]UCB-J binding to SV2A; and Ki or KiR to cerebellum for [18F]FDG metabolism. [11C]UCB-J binding and [18F]FDG metabolism showed a similar magnitude of reduction in the medial temporal lobe of AD -compared to CN participants. However, the magnitude of reduction of [11C]UCB-J binding in neocortical regions was less than that observed with [18F]FDG metabolism. Inter-tracer correlations were also higher in the medial temporal regions between synaptic density and metabolism, with lower correlations in neocortical regions. [11C]UCB-J perfusion showed a similar pattern to [18F]FDG metabolism, with high inter-tracer regional correlations. In summary, we conducted the first in vivo PET imaging of synaptic density and metabolism in the same AD participants and reported a concordant reduction in medial temporal regions but a discordant reduction in neocortical regions.



J Cereb Blood Flow Metab: 23 Mar 2021:271678X211004312; epub ahead of print
Chen MK, Mecca AP, Naganawa M, Gallezot JD, ... van Dyck CH, Carson RE
J Cereb Blood Flow Metab: 23 Mar 2021:271678X211004312; epub ahead of print | PMID: 33757318
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Impact:
Abstract

Deep white matter hyperintensity is associated with the dilation of perivascular space.

Huang P, Zhang R, Jiaerken Y, Wang S, ... Wu X, Zhang M
Understanding the pathophysiology of white matter hyperintensity (WMH) is necessary to reduce its harmfulness. Dilated perivascular space (PVS) had been found related to WMH. In the present study, we aimed to examine the topological connections between WMH and PVS, and to investigate whether increased interstitial fluid mediates the correlation between PVS and WMH volumes. One hundred and thirty-six healthy elder subjects were retrospectively included from a prospectively collected community cohort. Sub-millimeter T2 weighted and FLAIR images were acquired for assessing the association between PVS and WMH. Diffusion tensor imaging and free-water (FW) analytical methods were used to quantify white matter free water content, and to explore whether it mediates the PVS-WMH association. We found that most (89%) of the deep WMH lesions were spatially connected with PVS, exhibiting several interesting topological types. PVS and WMH volumes were also significantly correlated (r = 0.222, p < 0.001). FW mediated this association in the whole sample (β = 0.069, p = 0.037) and in subjects with relatively high WMH load (β = 0.118, p = 0.006). These findings suggest a tight association between PVS dilation and WMH formation, which might be linked by the impaired glymphatic drainage function and accumulated local interstitial fluid.



J Cereb Blood Flow Metab: 23 Mar 2021:271678X211002279; epub ahead of print
Huang P, Zhang R, Jiaerken Y, Wang S, ... Wu X, Zhang M
J Cereb Blood Flow Metab: 23 Mar 2021:271678X211002279; epub ahead of print | PMID: 33757317
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Impact:
Abstract

Urokinase-type plasminogen activator promotes N-cadherin-mediated synaptic recovery in the ischemic brain.

Diaz A, Merino P, McCann P, Yepes MA, ... Tong FC, Yepes M
Urokinase-type plasminogen activator (uPA) is a serine proteinase that catalyzes the generation of plasmin on the cell surface and activates cell signaling pathways that promote remodeling and repair. Neuronal cadherin (NCAD) is a transmembrane protein that in the mature brain mediates the formation of synaptic contacts in the II/III and V cortical layers. Our studies show that uPA is preferentially found in the II/III and V cortical laminae of the gyrencephalic cortex of the non-human primate. Furthermore, we found that in murine cerebral cortical neurons and induced pluripotent stem cell (iPSC)-derived neurons prepared from healthy human donors, most of this uPA is associated with pre-synaptic vesicles. Our in vivo experiments revealed that in both, the gyrencephalic cortex of the non-human primate and the lissecephalic murine brain, cerebral ischemia decreases the number of intact synaptic contacts and the expression of uPA and NCAD in a band of tissue surrounding the necrotic core. Additionally, our in vitro data show that uPA induces the synthesis of NCAD in cerebral cortical neurons, and in line with these observations, intravenous treatment with recombinant uPA three hours after the onset of cerebral ischemia induces NCAD-mediated repair of synaptic contacts in the area surrounding the necrotic core.



J Cereb Blood Flow Metab: 23 Mar 2021:271678X211002297; epub ahead of print
Diaz A, Merino P, McCann P, Yepes MA, ... Tong FC, Yepes M
J Cereb Blood Flow Metab: 23 Mar 2021:271678X211002297; epub ahead of print | PMID: 33757316
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Impact:
Abstract

Periinfarct rewiring supports recovery after primary motor cortex stroke.

van Assche M, Dirren E, Bourgeois A, Kleinschmidt A, Richiardi J, Carrera E
After stroke restricted to the primary motor cortex (M1), it is uncertain whether network reorganization associated with recovery involves the periinfarct or more remote regions. We studied 16 patients with focal M1 stroke and hand paresis. Motor function and resting-state MRI functional connectivity (FC) were assessed at three time points: acute (<10 days), early subacute (3 weeks), and late subacute (3 months). FC correlates of recovery were investigated at three spatial scales, (i) ipsilesional non-infarcted M1, (ii) core motor network (M1, premotor cortex (PMC), supplementary motor area (SMA), and primary somatosensory cortex), and (iii) extended motor network including all regions structurally connected to the upper limb representation of M1. Hand dexterity was impaired only in the acute phase (P = 0.036). At a small spatial scale, clinical recovery was more frequently associated with connections involving ipsilesional non-infarcted M1 (Odds Ratio = 6.29; P = 0.036). At a larger scale, recovery correlated with increased FC strength in the core network compared to the extended motor network (rho = 0.71;P = 0.006). These results suggest that FC changes associated with motor improvement involve the perilesional M1 and do not extend beyond the core motor network. Core motor regions, and more specifically ipsilesional non-infarcted M1, could hence become primary targets for restorative therapies.



J Cereb Blood Flow Metab: 23 Mar 2021:271678X211002968; epub ahead of print
van Assche M, Dirren E, Bourgeois A, Kleinschmidt A, Richiardi J, Carrera E
J Cereb Blood Flow Metab: 23 Mar 2021:271678X211002968; epub ahead of print | PMID: 33757315
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Impact:
Abstract

Preclinical and clinical evidence of IGF-1 as a prognostic marker and acute intervention with ischemic stroke.

Hayes CA, Valcarcel-Ares MN, Ashpole NM
Ischemic strokes are highly prevalent in the elderly population and are a leading cause of mortality and morbidity worldwide. The risk of ischemic stroke increases in advanced age, corresponding with a noted decrease in circulating insulin growth factor-1 (IGF-1). IGF-1 is a known neuroprotectant involved in embryonic development, neurogenesis, neurotransmission, cognition, and lifespan. Clinically, several studies have shown that reduced levels of IGF-1 correlate with increased mortality rate, poorer functional outcomes, and increased morbidities following an ischemic stroke. In animal models of ischemia, administering exogenous IGF-1 using various routes of administration (intranasal, intravenous, subcutaneous, or topical) at various time points prior to and following insult attenuates neurological damage and accompanying behavioral changes caused by ischemia. However, there are some contrasting findings in select clinical and preclinical studies. This review discusses the role of IGF-1 as a determinant factor of ischemic stroke outcomes, both within the clinical settings and preclinical animal models. Furthermore, the review provides insight on the role of IGF-1 in mechanisms and cellular processes that contribute to stroke damage.



J Cereb Blood Flow Metab: 23 Mar 2021:271678X211000894; epub ahead of print
Hayes CA, Valcarcel-Ares MN, Ashpole NM
J Cereb Blood Flow Metab: 23 Mar 2021:271678X211000894; epub ahead of print | PMID: 33757314
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Abstract

Telmisartan prevents high-fat diet-induced neurovascular impairments and reduces anxiety-like behavior.

Huber G, Ogrodnik M, Wenzel J, Stölting I, ... Jurk D, Raasch W
Angiotensin II receptor blockers (telmisartan) prevent rodents from diet-induced obesity and improve their metabolic status. Hyperglycemia and obesity are associated with reduced cerebral blood flow and neurovascular uncoupling which may lead to behavioral deficits. We wanted to know whether a treatment with telmisartan prevents these changes in obesity.We put young mice on high-fat diet and simultaneously treated them with telmisartan. At the end of treatment, we performed laser speckle imaging and magnetic resonance imaging to assess the effect on neurovascular coupling and cerebral blood flow. Different behavioral tests were used to investigate cognitive function.Mice developed diet-induced obesity and after 16, not 8 weeks of high-fat diet, however, the response to whisker pad stimulation was about 30% lower in obese compared to lean mice. Simultaneous telmisartan treatment increased the response again by 10% compared to obese mice. Moreover, telmisartan treatment normalized high-fat diet-induced reduction of cerebral blood flow and prevented a diet-induced anxiety-like behavior. In addition to that, telmisartan affects cellular senescence and string vessel formation in obesity.We conclude, that telmisartan protects against neurovascular unit impairments in a diet-induced obesity setting and may play a role in preventing obesity related cognitive deficits in Alzheimer\'s disease.



J Cereb Blood Flow Metab: 16 Mar 2021:271678X211003497; epub ahead of print
Huber G, Ogrodnik M, Wenzel J, Stölting I, ... Jurk D, Raasch W
J Cereb Blood Flow Metab: 16 Mar 2021:271678X211003497; epub ahead of print | PMID: 33730932
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Abstract

Global proteomic analysis of extracellular matrix in mouse and human brain highlights relevance to cerebrovascular disease.

Pokhilko A, Brezzo G, Handunnetthi L, Heilig R, ... Horsburgh K, Cader MZ
The extracellular matrix (ECM) is a key interface between the cerebrovasculature and adjacent brain tissues. Deregulation of the ECM contributes to a broad range of neurological disorders. However, despite this importance, our understanding of the ECM composition remains very limited mainly due to difficulties in its isolation. To address this, we developed an approach to extract the cerebrovascular ECM from mouse and human post-mortem normal brain tissues. We then used mass spectrometry with off-line high-pH reversed-phase fractionation to increase the protein detection. This identified more than 1000 proteins in the ECM-enriched fraction, with > 66% of the proteins being common between the species. We report 147 core ECM proteins of the human brain vascular matrisome, including collagens, laminins, fibronectin and nidogens. We next used network analysis to identify the connection between the brain ECM proteins and cerebrovascular diseases. We found that genes related to cerebrovascular diseases, such as COL4A1, COL4A2, VCAN and APOE were significantly enriched in the cerebrovascular ECM network. This provides unique mechanistic insight into cerebrovascular disease and potential drug targets. Overall, we provide a powerful resource to study the functions of brain ECM and highlight a specific role for brain vascular ECM in cerebral vascular disease.



J Cereb Blood Flow Metab: 16 Mar 2021:271678X211004307; epub ahead of print
Pokhilko A, Brezzo G, Handunnetthi L, Heilig R, ... Horsburgh K, Cader MZ
J Cereb Blood Flow Metab: 16 Mar 2021:271678X211004307; epub ahead of print | PMID: 33730931
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Abstract

Targeting neutrophils as a novel therapeutic strategy after stroke.

Chen C, Huang T, Zhai X, Ma Y, ... Yin J, Li P
Stroke is followed by an intricate immune interaction involving the engagement of multiple immune cells, including neutrophils. As one of the first responders recruited to the brain, the crucial roles of neutrophils in the ischemic brain damage are receiving increasing attention in recent years. Notably, neutrophils are not homogenous, and yet there is still a lack of full knowledge about the extent and impact of neutrophil heterogeneity. The biological understanding of the neutrophil response to both innate and pathological conditions is rapidly evolving as single-cell-RNA sequencing uncovers overall neutrophil profiling across maturation and differentiation contexts. In this review, we scrutinize the latest research that points to the multifaceted role of neutrophils in different conditions and summarize the regulatory signals that may determine neutrophil diversity. In addition, we list several potential targets or therapeutic strategies targeting neutrophils to limit brain damage following ischemic stroke.



J Cereb Blood Flow Metab: 09 Mar 2021:271678X211000137; epub ahead of print
Chen C, Huang T, Zhai X, Ma Y, ... Yin J, Li P
J Cereb Blood Flow Metab: 09 Mar 2021:271678X211000137; epub ahead of print | PMID: 33691513
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Abstract

Crossed cerebellar diaschisis on F-FDG PET: Frequency across neurodegenerative syndromes and association with C-PIB and F-Flortaucipir.

Provost K, La Joie R, Strom A, Iaccarino L, ... Jagust WJ, Rabinovici GD
We used 18F-FDG-PET to investigate the frequency of crossed cerebellar diaschisis (CCD) in 197 patients with various syndromes associated with neurodegenerative diseases. In a subset of 117 patients, we studied relationships between CCD and cortical asymmetry of Alzheimer\'s pathology (β-amyloid (11C-PIB) and tau (18F-Flortaucipir)). PET images were processed using MRIs to derive parametric SUVR images and define regions of interest. Indices of asymmetry were calculated in the cerebral cortex, basal ganglia and cerebellar cortex. Across all patients, cerebellar 18F-FDG asymmetry was associated with reverse asymmetry of 18F-FDG in the cerebral cortex (especially frontal and parietal areas) and basal ganglia. Based on our operational definition (cerebellar asymmetry >3% with contralateral supratentorial hypometabolism), significant CCD was present in 47/197 (24%) patients and was most frequent in corticobasal syndrome and semantic and logopenic variants of primary progressive aphasia. In β-amyloid-positive patients, mediation analyses showed that 18F-Flortaucipir cortical asymmetry was associated with cerebellar 18F-FDG asymmetry, but that cortical 18F-FDG asymmetry mediated this relationship. Analysis of 18F-FDG-SUVR values suggested that CCD might also occur in the absence of frank cerebellar 18F-FDG asymmetry due to symmetrical supratentorial degeneration resulting in a bilateral diaschisis process.



J Cereb Blood Flow Metab: 09 Mar 2021:271678X211001216; epub ahead of print
Provost K, La Joie R, Strom A, Iaccarino L, ... Jagust WJ, Rabinovici GD
J Cereb Blood Flow Metab: 09 Mar 2021:271678X211001216; epub ahead of print | PMID: 33691512
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Abstract

Transcriptome analysis reveals sexual disparities in gene expression in rat brain microvessels.

Chandra PK, Cikic S, Baddoo MC, Rutkai I, ... Katakam PV, Busija DW
Sex is an important determinant of brain microvessels (MVs) function and susceptibility to cerebrovascular and neurological diseases, but underlying mechanisms are unclear. Using high throughput RNA sequencing analysis, we examined differentially expressed (DE) genes in brain MVs from young, male, and female rats. Bioinformatics analysis of the 23,786 identified genes indicates that 298 (1.2%) genes were DE using False Discovery Rate criteria (FDR; p < 0.05), of which 119 (40%) and 179 (60%) genes were abundantly expressed in male and female MVs, respectively. Nucleic acid binding, enzyme modulator, and transcription factor were the top three DE genes, which were more highly expressed in male than female MVs. Synthesis of glycosylphosphatidylinositol (GPI), biosynthesis of GPI-anchored proteins, steroid and cholesterol synthesis, were the top three significantly enriched canonical pathways in male MVs. In contrast, respiratory chain, ribosome, and 3 ́-UTR-mediated translational regulation were the top three enriched canonical pathways in female MVs. Different gene functions of MVs were validated by proteomic analysis and western blotting. Our novel findings reveal major sex disparities in gene expression and canonical pathways of MVs and these differences provide a foundation to study the underlying mechanisms and consequences of sex-dependent differences in cerebrovascular and other neurological diseases.



J Cereb Blood Flow Metab: 08 Mar 2021:271678X21999553; epub ahead of print
Chandra PK, Cikic S, Baddoo MC, Rutkai I, ... Katakam PV, Busija DW
J Cereb Blood Flow Metab: 08 Mar 2021:271678X21999553; epub ahead of print | PMID: 33715494
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Abstract

Activation of astroglial CB1R mediates cerebral ischemic tolerance induced by electroacupuncture.

Yang C, Liu J, Wang J, Yin A, ... Wang F, Xiong L
There are no effective treatments for stroke. The activation of endogenous protective mechanisms is a promising therapeutic approach, which evokes the intrinsic ability of the brain to protect itself. Accumulated evidence strongly suggests that electroacupuncture (EA) pretreatment induces rapid tolerance to cerebral ischemia. With regard to mechanisms underlying ischemic tolerance induced by EA, many molecules and signaling pathways are involved, such as the endocannabinoid system, although the exact mechanisms have not been fully elucidated. In the current study, we employed mutant mice, neuropharmacology, microdialysis, and virus transfection techniques in a middle cerebral artery occlusion (MCAO) model to explore the cell-specific and brain region-specific mechanisms of EA-induced neuroprotection. EA pretreatment resulted in increased ambient endocannabinoid (eCB) levels and subsequent activation of ischemic penumbral astroglial cannabinoid type 1 receptors (CB1R) which led to moderate upregulation of extracellular glutamate that protected neurons from cerebral ischemic injury. These findings provide a novel cellular mechanism of EA and a potential therapeutic target for ischemic stroke.



J Cereb Blood Flow Metab: 03 Mar 2021:271678X21994395; epub ahead of print
Yang C, Liu J, Wang J, Yin A, ... Wang F, Xiong L
J Cereb Blood Flow Metab: 03 Mar 2021:271678X21994395; epub ahead of print | PMID: 33663269
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Abstract

Brain energy metabolism in intracerebroventricularly administered streptozotocin mouse model of Alzheimer\'s disease: A H-[C]-NMR study.

Soni ND, Ramesh A, Roy D, Patel AB
Alzheimer\'s disease (AD) is a very common neurodegenerative disorder. Although a majority of the AD cases are sporadic, most of the studies are conducted using transgenic models. Intracerebroventricular (ICV) administered streptozotocin (STZ) animals have been used to explore mechanisms in sporadic AD. In this study, we have investigated memory and neurometabolism of ICV-STZ-administered C57BL6/J mice. The neuronal and astroglial metabolic activity was measured in 1H-[13C]-NMR spectrum of cortical and hippocampal tissue extracts of mice infused with [1,6-13C2]glucose and [2-13C]acetate, respectively. STZ-administered mice exhibited reduced (p = 0.00002) recognition index for memory. The levels of creatine, GABA, glutamate and NAA were reduced (p ≤ 0.04), while that of myo-inositol was increased (p < 0.05) in STZ-treated mice. There was a significant (p ≤ 0.014) reduction in aspartate-C3, glutamate-C4/C3, GABA-C2 and glutamine-C4 labeling from [1,6-13C2]glucose. This resulted in decreased rate of glucose oxidation in the cerebral cortex (0.64 ± 0.05 vs. 0.77 ± 0.05 µmol/g/min, p = 0.0008) and hippocampus (0.60 ± 0.04 vs. 0.73 ± 0.07 µmol/g/min, p = 0.001) of STZ-treated mice, due to similar reductions of glucose oxidation in glutamatergic and GABAergic neurons. Additionally, reduced glutamine-C4 labeling points towards compromised synaptic neurotransmission in STZ-treated mice. These data suggest that the ICV-STZ model exhibits neurometabolic deficits typically observed in AD, and its utility in understanding the mechanism of sporadic AD.



J Cereb Blood Flow Metab: 02 Mar 2021:271678X21996176; epub ahead of print
Soni ND, Ramesh A, Roy D, Patel AB
J Cereb Blood Flow Metab: 02 Mar 2021:271678X21996176; epub ahead of print | PMID: 33657898
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Abstract

Rbfox-1 contributes to CaMKIIα expression and intracerebral hemorrhage-induced secondary brain injury via blocking micro-RNA-124.

Shen F, Xu X, Yu Z, Li H, ... Shen M, Chen G
RNA-binding protein fox-1 homolog 1 (Rbfox-1), an RNA-binding protein in neurons, is thought to be associated with many neurological diseases. To date, the mechanism on which Rbfox-1 worsens secondary cell death in ICH remains poorly understood. In this study, we aimed to explore the role of Rbfox-1 in intracerebral hemorrhage (ICH)-induced secondary brain injury (SBI) and to identify its underlying mechanisms. We found that the expression of Rbfox-1 in neurons was significantly increased after ICH, which was accompanied by increases in the binding of Rbfox-1 to Ca2+/calmodulin-dependent protein kinase II (CaMKIIα) mRNA and the protein level of CaMKIIα. In addition, when exposed to exogenous upregulation or downregulation of Rbfox-1, the protein level of CaMKIIα showed a concomitant trend in brain tissue, which further suggested that CaMKIIα is a downstream-target protein of Rbfox-1. The upregulation of both proteins caused intracellular-Ca2+ overload and neuronal degeneration, which exacerbated brain damage. Furthermore, we found that Rbfox-1 promoted the expression of CaMKIIα via blocking the binding of micro-RNA-124 to CaMKIIα mRNA. Thus, Rbfox-1 is expected to be a promising therapeutic target for SBI after ICH.



J Cereb Blood Flow Metab: 27 Feb 2021; 41:530-545
Shen F, Xu X, Yu Z, Li H, ... Shen M, Chen G
J Cereb Blood Flow Metab: 27 Feb 2021; 41:530-545 | PMID: 32248729
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Abstract

Simulating the effect of cerebral blood flow changes on regional quantification of [F]flutemetamol and [F]florbetaben studies.

Heeman F, Yaqub M, Lopes Alves I, Heurling K, ... Lammertsma AA, AMYPAD Consortium
Global and regional changes in cerebral blood flow (CBF) can result in biased quantitative estimates of amyloid load by PET imaging. Therefore, the current simulation study assessed effects of these changes on amyloid quantification using a reference tissue approach for [18F]flutemetamol and [18F]florbetaben. Previously validated pharmacokinetic rate constants were used to simulate time-activity curves (TACs) corresponding to full dynamic and dual-time-window acquisition protocols. CBF changes were simulated by varying the tracer delivery (K1) from +25 to -25%. The standardized uptake value ratio (SUVr) was computed and TACs were fitted using reference Logan (RLogan) and the simplified reference tissue model (SRTM) to obtain the relative delivery rate (R1) and volume of distribution ratio (DVR). RLogan was least affected by CBF changes (χ2 = 583 p <0.001, χ2 = 81 p <0.001, for [18F]flutemetamol and [18F]florbetaben, respectively) and the extent of CBF sensitivity generally increased for higher levels of amyloid. Further, SRTM-derived R1 changes correlated well with simulated CBF changes (R2 > 0.95) and SUVr\'s sensitivity to CBF changes improved for later uptake-times, with the exception of [18F]flutemetamol cortical changes. In conclusion, RLogan is the preferred method for amyloid quantification of [18F]flutemetamol and [18F]florbetaben studies and SRTM could be additionally used for obtaining a CBF proxy.



J Cereb Blood Flow Metab: 27 Feb 2021; 41:579-589
Heeman F, Yaqub M, Lopes Alves I, Heurling K, ... Lammertsma AA, AMYPAD Consortium
J Cereb Blood Flow Metab: 27 Feb 2021; 41:579-589 | PMID: 32281514
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Abstract

Reduced oxygen extraction efficiency in sickle cell anemia patients with evidence of cerebral capillary shunting.

Juttukonda MR, Donahue MJ, Waddle SL, Davis LT, ... Kassim AA, Jordan LC
Arterial spin labeling (ASL) magnetic resonance imaging (MRI) utilizes arterial blood water as an endogenous contrast agent to provide a quantitative measure of cerebral blood flow (CBF). Recently, hyperintense signal within dural venous sinuses in ASL images of sickle cell anemia (SCA) patients has been shown to be consistent with elevated flow velocities and may indicate capillary shunting and reduced oxygen extraction. Here, we performed oxygen extraction fraction (OEF) and CBF measurements in adults (cumulative n = 114) with (n = 69) and without (n = 45) SCA to test the hypothesis that hyperintense venous ASL signal is associated with reduced OEF. Higher categorical scores of shunting on ASL MRI were associated with lower OEF in participants with silent cerebral infarcts or white matter hyperintensities (p = 0.003), but not in those without lesions (p = 0.551). These findings indicate that venous hyperintense signal in ASL images in SCA patients may represent a marker of capillary-level disturbances in oxygen exchange efficiency and small vessel pathology.



J Cereb Blood Flow Metab: 27 Feb 2021; 41:546-560
Juttukonda MR, Donahue MJ, Waddle SL, Davis LT, ... Kassim AA, Jordan LC
J Cereb Blood Flow Metab: 27 Feb 2021; 41:546-560 | PMID: 32281458
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Abstract

Brain deep medullary veins on 3-T MRI in a population-based cohort.

Ao DH, Zhang DD, Zhai FF, Zhang JT, ... Zhou LX, Zhu YC
Our aim is to investigate whether vascular risk factors are associated with cerebral deep medullary veins (DMVs) and whether DMVs are associated with MRI markers of cerebral small vessel disease (CSVD) or risk of stroke. In a community-based cohort of 1056 participants (mean age 55.7 years), DMVs were identified on susceptibility-weighted imaging (SWI) and counted in periventricular regions. Neuroimaging markers including lacunes, whiter matter hyperintensity (WMH), microbleeds, enlarged perivascular space, and brain atrophy were evaluated. The number of DMVs decreased with age (p = 0.007). After adjusting for age and sex, the number of DMVs was not associated with traditional vascular risk factors. Fewer DMVs was associated with increase of WMH and lacunes, but the association vanished after adjustment for vascular risk factors. However, fewer DMVs were independently associated with brain atrophy (p < 0.001). DMVs were not associated with three-year risk of stroke. Our results suggest that DMV is significantly different from other MRI markers of CSVD regarding risk factors, association with other CSVD markers, and risk of stroke. Nonetheless, the significant association between DMV and brain atrophy suggested the potential role of venules in age-related neurodegenerative process, which deserves further investigation.



J Cereb Blood Flow Metab: 27 Feb 2021; 41:561-568
Ao DH, Zhang DD, Zhai FF, Zhang JT, ... Zhou LX, Zhu YC
J Cereb Blood Flow Metab: 27 Feb 2021; 41:561-568 | PMID: 32312169
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Abstract

Repeatability of parametric methods for [F]florbetapir imaging in Alzheimer\'s disease and healthy controls: A test-retest study.

Verfaillie SC, Golla SS, Timmers T, Tuncel H, ... van Berckel BN, Boellaard R
Accumulation of amyloid beta (Aβ) is one of the pathological hallmarks of Alzheimer\'s disease (AD), which can be visualized using [18F]florbetapir positron emission tomography (PET). The aim of this study was to evaluate various parametric methods and to assess their test-retest (TRT) reliability. Two 90 min dynamic [18F]florbetapir PET scans, including arterial sampling, were acquired (n = 8 AD patient, n = 8 controls). The following parametric methods were used; (reference:cerebellum); Logan and spectral analysis (SA), receptor parametric mapping (RPM), simplified reference tissue model2 (SRTM2), reference Logan (rLogan) and standardized uptake value ratios (SUVr(50-70)). BPND+1, DVR, VT and SUVr were compared with corresponding estimates (VT or DVR) from the plasma input reversible two tissue compartmental (2T4k_VB) model with corresponding TRT values for 90-scan duration. RPM (r2 = 0.92; slope = 0.91), Logan (r2 = 0.95; slope = 0.84) and rLogan (r2 = 0.94; slope = 0.88), and SRTM2 (r2 = 0.91; slope = 0.83), SA (r2 = 0.91; slope = 0.88), SUVr (r2 = 0.84; slope = 1.16) correlated well with their 2T4k_VB counterparts. RPM (controls: 1%, AD: 3%), rLogan (controls: 1%, AD: 3%) and SUVr(50-70) (controls: 3%, AD: 8%) showed an excellent TRT reliability. In conclusion, most parametric methods showed excellent performance for [18F]florbetapir, but RPM and rLogan seem the methods of choice, combining the highest accuracy and best TRT reliability.



J Cereb Blood Flow Metab: 27 Feb 2021; 41:569-578
Verfaillie SC, Golla SS, Timmers T, Tuncel H, ... van Berckel BN, Boellaard R
J Cereb Blood Flow Metab: 27 Feb 2021; 41:569-578 | PMID: 32321347
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Abstract

TET3 regulates DNA hydroxymethylation of neuroprotective genes following focal ischemia.

Morris-Blanco KC, Chokkalla AK, Bertogliat MJ, Vemuganti R
The 5-hydroxymethylcytosine (5hmC) epigenetic modification is highly enriched in the CNS and a critical modulator of neuronal function and development. We found that cortical 5hmC was enhanced from 5 min to three days of reperfusion following focal ischemia in adult mice. Blockade of the 5hmC-producing enzyme ten-eleven translocase 3 (TET3) increased edema, infarct volume, and motor function impairments. To determine the mechanism by which TET3 provides ischemic neuroprotection, we assessed the genomic regions where TET3 modulates 5hmC. Genome-wide sequencing analysis of differentially hydroxymethylated regions (DhMRs) revealed that focal ischemia robustly increased 5hmC at the promoters of thousands of genes in a TET3-dependent manner. TET3 inhibition reduced 5hmC at the promoters of neuroprotective genes involved in cell survival, angiogenesis, neurogenesis, antioxidant defense, DNA repair, and metabolism demonstrating a role for TET3 in endogenous protection against stroke. The mRNA expression of several genes with known involvement in ischemic neuroprotection were also reduced with TET3 knockdown in both male and female mice, establishing a correlation between decreased promoter 5hmC levels and decreased gene expression. Collectively, our results indicate that TET3 globally increases 5hmC at regulatory regions and overwhelmingly modulates 5hmC in several neuroprotective pathways that may improve outcome after ischemic injury.



J Cereb Blood Flow Metab: 27 Feb 2021; 41:590-603
Morris-Blanco KC, Chokkalla AK, Bertogliat MJ, Vemuganti R
J Cereb Blood Flow Metab: 27 Feb 2021; 41:590-603 | PMID: 32380888
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Abstract

CD36 deficiency reduces chronic BBB dysfunction and scar formation and improves activity, hedonic and memory deficits in ischemic stroke.

Balkaya M, Kim ID, Shakil F, Cho S
Ameliorating blood-brain barrier disruption and altering scar formation dynamics are potential strategies that may improve post-stroke recovery. CD36 is a class B scavenger receptor that plays a role in innate immunity, inflammation and vascular dysfunction and regulates post-stroke injury, neovascularization, reactive astrogliosis and scar formation. By subjecting WT and CD36KO mice to different MCAo occlusion durations to generate comparable acute lesion sizes, we addressed the role of CD36 in BBB dysfunction, scar formation and recovery. The majority of stroke recovery studies primarily focus on motor function. Here, we employed an extensive behavioral test arsenal to evaluate psychological and cognitive endpoints. While not evident during the acute phase, CD36 deficient mice displayed significantly attenuated BBB leakage and scar formation at three months after stroke compared to wild-type littermates. Assessment of motor (open field, rotarod), anxiety (plus maze, light-dark box), depression (forced swim, sucrose preference) and memory tests (water maze) revealed that CD36 deficiency ameliorated stroke-induced behavioral impairments in activity, hedonic responses and spatial learning and strategy switching. Our findings indicate that CD36 contributes to stroke-induced BBB dysfunction and scar formation in an injury-independent manner, as well as to the chronic motor and neurophysiological deficits in chronic stroke.



J Cereb Blood Flow Metab: 27 Feb 2021; 41:486-501
Balkaya M, Kim ID, Shakil F, Cho S
J Cereb Blood Flow Metab: 27 Feb 2021; 41:486-501 | PMID: 32404022
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Abstract

The cellular basis of increased PET hypoxia tracer uptake in focal cerebral ischemia with comparison between [F]FMISO and [Cu]CuATSM.

Little PV, Arnberg F, Jussing E, Lu L, ... Tran TA, Holmin S
PET hypoxia imaging can assess tissue viability in acute ischemic stroke (AIS). [18F]FMISO is an established tracer but requires substantial accumulation time, limiting its use in hyperacute AIS. [64Cu]CuATSM requires less accumulation time and has shown promise as a hypoxia tracer. We compared these tracers in a M2-occlusion model (M2CAO) with preserved collateral blood flow. Rats underwent M2CAO and [18F]FMISO (n = 12) or [64Cu]CuATSM (n = 6) examinations. [64Cu]CuATSM animals were also examined with MRI. Pimonidazole was used as a surrogate for [18F]FMISO in an immunofluorescence analysis employed to profile levels of hypoxia in neurons (NeuN) and astrocytes (GFAP). There was increased [18F]FMISO uptake in the M2CAO cortex. No increase in [64Cu]CuATSM activity was found. The pimonidazole intensity of neurons and astrocytes was increased in hypoxic regions. The pimonidazole intensity ratio was higher in neurons than in astrocytes. In the majority of animals, immunofluorescence revealed a loss of astrocytes within the core of regions with increased pimonidazole uptake. We conclude that [18F]FMISO is superior to [64Cu]CuATSM in detecting hypoxia in AIS, consistent with an earlier study. [18F]FMISO may provide efficient diagnostic imaging beyond the hyperacute phase. Results do not provide encouragement for the use of [64Cu]CuATSM in experimental AIS.



J Cereb Blood Flow Metab: 27 Feb 2021; 41:617-629
Little PV, Arnberg F, Jussing E, Lu L, ... Tran TA, Holmin S
J Cereb Blood Flow Metab: 27 Feb 2021; 41:617-629 | PMID: 32423333
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Abstract

Glutamate levels and perfusion in pons during migraine attacks: A 3T MRI study using proton spectroscopy and arterial spin labeling.

Younis S, Christensen CE, Vestergaard MB, Lindberg U, ... Hougaard A, Ashina M
Migraine is a complex disorder, involving peripheral and central brain structures, where mechanisms and site of attack initiation are an unresolved puzzle. While abnormal pontine neuronal activation during migraine attacks has been reported, exact implication of this finding is unknown. Evidence suggests an important role of glutamate in migraine, implying a possible association of pontine hyperactivity to increased glutamate levels. Migraine without aura patients were scanned during attacks after calcitonin gene-related peptide and sildenafil in a double-blind, randomized, double-dummy, cross-over design, on two separate study days, by proton magnetic resonance spectroscopy and pseudo-continuous arterial spin labeling at 3T. Headache characteristics were recorded until 24 h after drug administrations. Twenty-six patients were scanned during migraine, yielding a total of 41 attacks. Cerebral blood flow increased in dorsolateral pons, ipsilateral to pain side during attacks, compared to outside attacks (13.6%, p = 0.009). Glutamate levels in the same area remained unchanged during attacks (p = 0.873), while total creatine levels increased (3.5%, p = 0.041). In conclusion, dorsolateral pontine activation during migraine was not associated with higher glutamate levels. However, the concurrently increased total creatine levels may suggest an altered energy metabolism, which should be investigated in future studies to elucidate the role of pons in acute migraine.



J Cereb Blood Flow Metab: 27 Feb 2021; 41:604-616
Younis S, Christensen CE, Vestergaard MB, Lindberg U, ... Hougaard A, Ashina M
J Cereb Blood Flow Metab: 27 Feb 2021; 41:604-616 | PMID: 32423331
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Abstract

Developmental patterns of CBF and BOLD responses to visual stimulus.

Zou P, Scoggins MA, Li Y, Jones M, Helton KJ, Ogg RJ
To investigate the developmental changes of cerebral blood flow (CBF) and hemodynamic responses to changing neural activity, we used the arterial spin label (ASL) technique to measure resting CBF and simultaneous CBF / blood-oxygen-level dependent (BOLD) signal changes during visual stimulation in 97 typically developing children and young adults (age 13.35 [6.02, 25.25] (median [min, max]) years old at the first time point). The longitudinal study protocol included three MRIs (2.7 ± 0.06 obtained), one year apart, for each participant. Mixed-effect linear and non-linear statistical models were used to analyze age effects on CBF and BOLD signals. Resting CBF decreased exponentially with age (p = 0.0001) throughout the brain, and developmental trajectories differed across brain lobes. The absolute CBF increase in visual cortex during stimulation was constant over the age range, but the fractional CBF change increased with age (p = 0.0001) and the fractional BOLD signal increased with age (p = 0.0001) correspondingly. These findings suggest that the apparent neural hemodynamic coupling in visual cortex does not change after age six years, but age-related BOLD signal changes continue through adolescence primarily due to the changes with age in resting CBF.



J Cereb Blood Flow Metab: 27 Feb 2021; 41:630-640
Zou P, Scoggins MA, Li Y, Jones M, Helton KJ, Ogg RJ
J Cereb Blood Flow Metab: 27 Feb 2021; 41:630-640 | PMID: 32436777
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Abstract

MicroRNA-30a regulates acute cerebral ischemia-induced blood-brain barrier damage through ZnT4/zinc pathway.

Wang P, Pan R, Weaver J, Jia M, ... Liang J, Liu KJ
The mechanism of early blood-brain barrier (BBB) disruption after stroke has been intensively studied but still not fully understood. Here, we report that microRNA-30a (miR-30a) could mediate BBB damage using both cellular and animal models of ischemic stroke. In the experiments in vitro, inhibition of miR-30a decreased BBB permeability, prevented the degradation of tight junction proteins, and reduced intracellular free zinc in endothelial cells. We found that the zinc transporter ZnT4 was a direct target of negative regulation by miR-30a, and ZnT4/zinc signaling pathway contributed significantly to miR-30a-mediated BBB damage. Consistent with these in vitro findings, treatment with miR-30a inhibitor reduced zinc accumulation, increased the expression of ZnT4, and prevented the loss of tight junction proteins in microvessels of ischemic animals. Furthermore, inhibition of miR-30a, even at 90 min post onset of middle cerebral artery occlusion, prevented BBB damage, reduced infarct volume, and ameliorated neurological deficits. Together, our findings provide novel insights into the mechanisms of cerebral ischemia-induced BBB disruption and indicate miR-30a as a regulator of BBB function that can be an effective therapeutic target for ischemic stroke.



J Cereb Blood Flow Metab: 27 Feb 2021; 41:641-655
Wang P, Pan R, Weaver J, Jia M, ... Liang J, Liu KJ
J Cereb Blood Flow Metab: 27 Feb 2021; 41:641-655 | PMID: 32501158
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Abstract

Simulation of oxygen transport and estimation of tissue perfusion in extensive microvascular networks: Application to cerebral cortex.

Celaya-Alcala JT, Lee GV, Smith AF, Li B, ... Boas DA, Secomb TW
Advanced imaging techniques have made available extensive three-dimensional microvascular network structures. Simulation of oxygen transport by such networks requires information on blood flow rates and oxygen levels in vessels crossing boundaries of the imaged region, which is difficult to obtain experimentally. Here, a computational method is presented for estimating blood flow rates, oxygen levels, tissue perfusion and oxygen extraction, based on incomplete boundary conditions. Flow rates in all segments are estimated using a previously published method. Vessels crossing the region boundary are classified as arterioles, capillaries or venules. Oxygen levels in inflowing capillaries are assigned based on values in outflowing capillaries, and similarly for venules. Convective and diffusive oxygen transport is simulated. Contributions of each vessel to perfusion are computed in proportion to the decline in oxygen concentration along that vessel. For a vascular network in the mouse cerebral cortex, predicted tissue oxygen levels show a broad distribution, with 99% of tissue in the range of 20 to 80 mmHg under reference conditions, and steep gradients near arterioles. Perfusion and extraction estimates are consistent with experimental values. A 30% reduction in perfusion or a 30% increase in oxygen demand, relative to reference levels, is predicted to result in tissue hypoxia.



J Cereb Blood Flow Metab: 27 Feb 2021; 41:656-669
Celaya-Alcala JT, Lee GV, Smith AF, Li B, ... Boas DA, Secomb TW
J Cereb Blood Flow Metab: 27 Feb 2021; 41:656-669 | PMID: 32501155
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Abstract

Cerebroarterial pulsatility and resistivity indices are associated with cognitive impairment and white matter hyperintensity in elderly subjects: A phase-contrast MRI study.

Pahlavian SH, Wang X, Ma S, Zheng H, ... Wang DJ, Yan L
Increased cerebroarterial pulsations are thought to be contributing factors in microvascular damage and cognitive impairment. In this study, we assessed the utility of two-dimensional (2D) phase-contrast MRI (PC-MRI) in quantifying cerebroarterial pulsations and evaluated the associations of pulsatile and non-pulsatile hemodynamic measures with cognitive performance and white matter hyperintensities (WMH). Neurocognitive assessments on 50 elderly subjects were performed using clinical dementia rating (CDR) and Montreal cognitive assessment (MoCA). An electrocardiogram-gated 2D PC-MRI sequence was used to calculate mean flow rate, pulsatility index (PI), and resistivity index (RI) of the internal carotid artery. For each subject, whole brain global cerebral blood flow (gCBF) and relative WMH volume were also quantified. Elevated RI was significantly associated with reduced cognitive performance quantified using MoCA (p =0.04) and global CDR (p =0.02). PI and RI were both significantly associated with relative WMH volume (p =0.01, p <0.01, respectively). However, non-pulsatile hemodynamic measures were not associated with cognitive impairment or relative WMH volume. This study showed that the cerebroarterial pulsatile measures obtained using PC-MRI have stronger association with the measures of cognitive impairment compared to global blood flow measurement and as such, might be useful as potential biomarkers of cerebrovascular dysfunction in preclinical populations.



J Cereb Blood Flow Metab: 27 Feb 2021; 41:670-683
Pahlavian SH, Wang X, Ma S, Zheng H, ... Wang DJ, Yan L
J Cereb Blood Flow Metab: 27 Feb 2021; 41:670-683 | PMID: 32501154
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Abstract

Integrating regional perfusion CT information to improve prediction of infarction after stroke.

Klug J, Dirren E, Preti MG, Machi P, ... Van De Ville D, Carrera E
Physiological evidence suggests that neighboring brain regions have similar perfusion characteristics (vascular supply, collateral blood flow). It is largely unknown whether integrating perfusion CT (pCT) information from the area surrounding a given voxel (i.e. the receptive field (RF)) improves the prediction of infarction of this voxel. Based on general linear regression models (GLMs) and using acute pCT-derived maps, we compared the added value of cuboid RF to predict the final infarct. To this aim, we included 144 stroke patients with acute pCT and follow-up MRI, used to delineate the final infarct. Overall, the performance of GLMs to predict the final infarct improved when using RF for all pCT maps (cerebral blood flow, cerebral blood volume, mean transit time and time-to-maximum of the tissue residual function (Tmax)). The highest performance was obtained with Tmax (glm(Tmax); AUC = 0.89 ± 0.03 with RF vs. 0.78 ± 0.02 without RF; p < 0.001) and with a model combining all perfusion parameters (glm(multi); AUC 0.89 ± 0.02 with RF vs. 0.79 ± 0.02 without RF; p < 0.001). These results suggest that prediction of infarction improves by integrating perfusion information from adjacent tissue. This approach may be applied in future studies to better identify ischemic core and penumbra thresholds and improve patient selection for acute stroke treatment.



J Cereb Blood Flow Metab: 27 Feb 2021; 41:502-510
Klug J, Dirren E, Preti MG, Machi P, ... Van De Ville D, Carrera E
J Cereb Blood Flow Metab: 27 Feb 2021; 41:502-510 | PMID: 32501132
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Abstract

Interleukin-4 improves white matter integrity and functional recovery after murine traumatic brain injury via oligodendroglial PPARγ.

Pu H, Zheng X, Jiang X, Mu H, ... Bennett MV, Chen J
Long-term neurological recovery after severe traumatic brain injury (TBI) is strongly linked to the repair and functional restoration of injured white matter. Emerging evidence suggests that the anti-inflammatory cytokine interleukin-4 (IL-4) plays an important role in promoting white matter integrity after cerebral ischemic injury. Here, we report that delayed intranasal delivery of nanoparticle-packed IL-4 boosted sensorimotor neurological recovery in a murine model of controlled cortical impact, as assessed by a battery of neurobehavioral tests for up to five weeks. Post-injury IL-4 treatment failed to reduce macroscopic brain lesions after TBI, but preserved the structural and functional integrity of white matter, at least in part through oligodendrogenesis. IL-4 directly facilitated the differentiation of oligodendrocyte progenitor cells (OPCs) into mature myelin-producing oligodendrocytes in primary cultures, an effect that was attenuated by selective PPARγ inhibition. IL-4 treatment after TBI in vivo also failed to stimulate oligodendrogenesis or improve white matter integrity in OPC-specific PPARγ conditional knockout (cKO) mice. Accordingly, IL-4-afforded improvements in sensorimotor neurological recovery after TBI were markedly impaired in the PPARγ cKO mice compared to wildtype controls. These results support IL-4 as a potential novel neurorestorative therapy to improve white matter functionality and mitigate the long-term neurological consequences of TBI.



J Cereb Blood Flow Metab: 27 Feb 2021; 41:511-529
Pu H, Zheng X, Jiang X, Mu H, ... Bennett MV, Chen J
J Cereb Blood Flow Metab: 27 Feb 2021; 41:511-529 | PMID: 32757740
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Abstract

Benefits of exercise training on cerebrovascular and cognitive function in ageing.

Bliss ES, Wong RH, Howe PR, Mills DE
Derangements in cerebrovascular structure and function can impair cognitive performance throughout ageing and in cardiometabolic disease states, thus increasing dementia risk. Modifiable lifestyle factors that cause a decline in cardiometabolic health, such as physical inactivity, exacerbate these changes beyond those that are associated with normal ageing. The purpose of this review was to examine cerebrovascular, cognitive and neuroanatomical adaptations to ageing and the potential benefits of exercise training on these outcomes in adults 50 years or older. We systematically searched for cross-sectional or intervention studies that included exercise (aerobic, resistance or multimodal) and its effect on cerebrovascular function, cognition and neuroanatomical adaptations in this age demographic. The included studies were tabulated and described narratively. Aerobic exercise training was the predominant focus of the studies identified; there were limited studies exploring the effects of resistance exercise training and multimodal training on cerebrovascular function and cognition. Collectively, the evidence indicated that exercise can improve cerebrovascular function, cognition and neuroplasticity through areas of the brain associated with executive function and memory in adults 50 years or older, irrespective of their health status. However, more research is required to ascertain the mechanisms of action.



J Cereb Blood Flow Metab: 27 Feb 2021; 41:447-470
Bliss ES, Wong RH, Howe PR, Mills DE
J Cereb Blood Flow Metab: 27 Feb 2021; 41:447-470 | PMID: 32954902
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Abstract

Principles and requirements for stroke recovery science.

Sommer CJ, Schäbitz WR
The disappointing results in bench-to-bedside translation of neuroprotective strategies caused a certain shift in stroke research towards enhancing the endogenous recovery potential of the brain. One reason for this focus on recovery is the much wider time window for therapeutic interventions which is open for at least several months. Since recently two large clinical studies using d-amphetamine or fluoxetine, respectively, to enhance post-stroke neurological outcome failed again it is a good time for a critical reflection on principles and requirements for stroke recovery science. In principal, stroke recovery science deals with all events from the molecular up to the functional and behavioral level occurring after brain ischemia eventually ending up with any measurable improvement of various clinical parameters. A detailed knowledge of the spontaneously occurring post-ischemic regeneration processes is the indispensable prerequisite for any therapeutic approaches aiming to modify these responses to enhance post-stroke recovery. This review will briefly illuminate the molecular mechanisms of post-ischemic regeneration and the principle possibilities to foster post-stroke recovery. In this context, recent translational approaches are analyzed. Finally, the principal and specific requirements and pitfalls in stroke recovery research as well as potential explanations for translational failures will be discussed.



J Cereb Blood Flow Metab: 27 Feb 2021; 41:471-485
Sommer CJ, Schäbitz WR
J Cereb Blood Flow Metab: 27 Feb 2021; 41:471-485 | PMID: 33175596
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Abstract

Circadian effects on stroke outcome - Did we not wake up in time for neuroprotection?

Boltze J, Didwischus N, Merrow M, Dallmann R, Plesnila N
The occurrence of stroke in humans peaks in the morning. A recent study revealed that time of day mitigates the therapeutic impact of neuroprotective paradigms. These findings might not only explain the previous failure of translation of neuroprotective therapies but inspire new paradigms in stroke chronopathophysiology research. Taking chronotype into account may complement the many factors that influence efficacy of experimental therapies in stroke.



J Cereb Blood Flow Metab: 27 Feb 2021; 41:684-686
Boltze J, Didwischus N, Merrow M, Dallmann R, Plesnila N
J Cereb Blood Flow Metab: 27 Feb 2021; 41:684-686 | PMID: 33337257
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Abstract

Change and predictive ability of circulating immunoregulatory lymphocytes in long-term outcomes of acute ischemic stroke.

Li S, Huang Y, Liu Y, Rocha M, ... Zhao J, Gao Y
Lymphocytes play an important role in the immune response after stroke. However, our knowledge of the circulating lymphocytes in ischemic stroke is limited. Herein, we collected the blood samples of clinical ischemic stroke patients to detect the change of lymphocytes from admission to 3 months after ischemic stroke by flow cytometry. A total of 87 healthy controls and 210 patients were enrolled, and the percentages of circulating T cells, CD4+ T cells, CD8+ T cells, double negative T cells (DNTs), CD4+ regulatory T cells (Tregs), CD8+ Tregs, B cells and regulatory B cells (Bregs) were measured. Among patients, B cells, Bregs and CD8+ Tregs increased significantly, while CD4+ Tregs dropped and soon reversed after ischemic stroke. CD4+ Tregs, CD8+ Tregs, and DNTs also showed high correlations with the infarct volume and neurological scores of patients. Moreover, these lymphocytes enhanced the predictive ability of long-term prognosis of neurological scores when added to basic clinical information. The percentage of CD4+ Tregs within lymphocytes showed high correlations with both acute and long-term neurological outcomes, which exhibited a great independent predictive ability. These findings suggest that CD4+ Tregs can be a biomarker to predict stroke outcomes and improve existing therapeutic strategies of immunoregulatory lymphocytes.



J Cereb Blood Flow Metab: 26 Feb 2021:271678X21995694; epub ahead of print
Li S, Huang Y, Liu Y, Rocha M, ... Zhao J, Gao Y
J Cereb Blood Flow Metab: 26 Feb 2021:271678X21995694; epub ahead of print | PMID: 33641517
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Abstract

Reduction of neuroinflammation alleviated mouse post bone fracture and stroke memory dysfunction.

Huo K, Wei M, Zhang M, Wang Z, ... Wong J, Su H
Tibia fracture (BF) enhances stroke injury and post-stroke memory dysfunction in mouse. Reduction of neuroinflammation by activation of α-7 nicotinic acetylcholine receptor (α-7 nAchR) reduced acute neuronal injury and sensorimotor dysfunction in mice with BF 1-day after stroke. We hypothesize that reduction of neuroinflammation by activation of α-7 nAchR improves long-term memory function of mice with BF 6-h before stroke. The mice were randomly assigned to saline, PHA-568487 (α-7 nAchR agonist) and methyllycaconitine (antagonist) treatment groups. The sensorimotor function was tested by adhesive removal and corner tests at 3 days, the memory function was tested by Y-maze test weekly for 8 weeks and novel objective recognition test at 8 weeks post-injuries. We found PHA-568487 treatment reduced, methyllycaconitine increased the number of CD68+ cells in the peri-infarct and hippocampal regions, neuronal injury in the infarct region, sensorimotor and long-term memory dysfunctions. PHA-568487 treatment also reduced, while methyllycaconitine treatment increased atrophy of hippocampal granule cell layer and white matter damage in the striatum. In addition, PHA-568487 treatment increased neuron proliferation in granule cell layer. Our data indicated that reduction of neuroinflammation through activation of α-7 nAchR decreased neuronal damage, sensorimotor and long-term memory dysfunction of mice with BF shortly before stroke.



J Cereb Blood Flow Metab: 26 Feb 2021:271678X21996177; epub ahead of print
Huo K, Wei M, Zhang M, Wang Z, ... Wong J, Su H
J Cereb Blood Flow Metab: 26 Feb 2021:271678X21996177; epub ahead of print | PMID: 33641516
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Abstract

Glymphatic pathways in the gyrencephalic brain.

Bèchet NB, Shanbhag NC, Lundgaard I
Identification of the perivascular compartment as the point of exchange between cerebrospinal fluid (CSF) and interstitial fluid mediating solute clearance in the brain, named the glymphatic system, has emerged as an important clearance pathway for neurotoxic peptides such as amyloid-beta. However, the foundational science of the glymphatic system is based on rodent studies. Here we investigated whether the glymphatic system exists in a large mammal with a highly gyrified brain. CSF penetration into the brain via perivascular pathways, a hallmark of glymphatic function, was seen throughout the gyrencephalic cortex and subcortical structures, validating the conservation of the glymphatic system in a large mammal. Macroscopic CSF tracer distribution followed the sulci and fissures showing that these folds enhance CSF dispersion. Three-dimensional renditions from light sheet microscopy showed a PVS influx density 4-fold larger in the pig brain than in mice. This demonstrates the existence of an advanced solute transport system in the gyrencephalic brain that could be utilised therapeutically for enhancing waste clearance.



J Cereb Blood Flow Metab: 26 Feb 2021:271678X21996175; epub ahead of print
Bèchet NB, Shanbhag NC, Lundgaard I
J Cereb Blood Flow Metab: 26 Feb 2021:271678X21996175; epub ahead of print | PMID: 33641515
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Abstract

Optical coherence tomography of arteriolar diameter and capillary perfusion during spreading depolarizations.

Anzabi M, Li B, Wang H, Kura S, ... Østergaard L, Ayata C
Spreading depolarization (SD) is associated with profound oligemia and reduced oxygen availability in the mouse cortex during the depolarization phase. Coincident pial arteriolar constriction has been implicated as the primary mechanism for the oligemia. However, where in the vascular bed the hemodynamic response starts has been unclear. To resolve the origin of the hemodynamic response, we used optical coherence tomography (OCT) to simultaneously monitor changes in the vascular tree from capillary bed to pial arteries in mice during two consecutive SDs 15 minutes apart. We found that capillary flow dropped several seconds before pial arteriolar constriction. Moreover, penetrating arterioles constricted before pial arteries suggesting upstream propagation of constriction. Smaller caliber distal pial arteries constricted stronger than larger caliber proximal arterioles, suggesting that the farther the constriction propagates, the weaker it gets. Altogether, our data indicate that the hemodynamic response to cortical SD originates in the capillary bed.



J Cereb Blood Flow Metab: 15 Feb 2021:271678X21994013; epub ahead of print
Anzabi M, Li B, Wang H, Kura S, ... Østergaard L, Ayata C
J Cereb Blood Flow Metab: 15 Feb 2021:271678X21994013; epub ahead of print | PMID: 33593116
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Abstract

ErbB3 is a critical regulator of cytoskeletal dynamics in brain microvascular endothelial cells: Implications for vascular remodeling and blood-brain-barrier modulation.

Wu L, Islam MR, Lee J, Takase H, ... Ramirez SH, Lok J
Neuregulin (NRG)1 - ErbB receptor signaling has been shown to play an important role in the biological function of peripheral microvascular endothelial cells. However, little is known about how NRG1/ErbB signaling impacts brain endothelial function and blood-brain barrier (BBB) properties. NRG1/ErbB pathways are affected by brain injury; when brain trauma was induced in mice in a controlled cortical impact model, endothelial ErbB3 gene expression was reduced to a greater extent than that of other NRG1 receptors. This finding suggests that ErbB3-mediated processes may be significantly compromised after injury, and that an understanding of ErbB3 function would be important in the of study of endothelial biology in the healthy and injured brain. Towards this goal, cultured brain microvascular endothelial cells were transfected with siRNA to ErbB3, resulting in alterations in F-actin organization and microtubule assembly, cell morphology, migration and angiogenic processes. Importantly, a significant increase in barrier permeability was observed when ErbB3 was downregulated, suggesting ErbB3 involvement in BBB regulation. Overall, these results indicate that neuregulin-1/ErbB3 signaling is intricately connected with the cytoskeletal processes of the brain endothelium and contributes to morphological and angiogenic changes as well as to BBB integrity.



J Cereb Blood Flow Metab: 13 Feb 2021:271678X20984976; epub ahead of print
Wu L, Islam MR, Lee J, Takase H, ... Ramirez SH, Lok J
J Cereb Blood Flow Metab: 13 Feb 2021:271678X20984976; epub ahead of print | PMID: 33583260
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Abstract

Effects of mild hypoxia on oxygen extraction fraction responses to brain stimulation.

Yin Y, Shu S, Qin L, Shan Y, Gao JH, Lu J
Characterizing the effect of limited oxygen availability on brain metabolism during brain activation is an essential step towards a better understanding of brain homeostasis and has obvious clinical implications. However, how the cerebral oxygen extraction fraction (OEF) depends on oxygen availability during brain activation remains unclear, which is mostly attributable to the scarcity and safety of measurement techniques. Recently, a magnetic resonance imaging (MRI) method that enables noninvasive and dynamic measurement of the OEF has been developed and confirmed to be applicable to functional MRI studies. Using this novel method, the present study investigated the motor-evoked OEF response in both normoxia (21% O2) and hypoxia (12% O2). Our results showed that OEF activation decreased in the brain areas involved in motor task execution. Decreases in the motor-evoked OEF response were greater under hypoxia (-21.7% ± 5.5%) than under normoxia (-11.8% ± 3.7%) and showed a substantial decrease as a function of arterial oxygen saturation. These findings suggest a different relationship between oxygen delivery and consumption during hypoxia compared to normoxia. This methodology may provide a new perspective on the effects of mild hypoxia on brain function.



J Cereb Blood Flow Metab: 08 Feb 2021:271678X21992896; epub ahead of print
Yin Y, Shu S, Qin L, Shan Y, Gao JH, Lu J
J Cereb Blood Flow Metab: 08 Feb 2021:271678X21992896; epub ahead of print | PMID: 33563081
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Abstract

Flow induces barrier and glycocalyx-related genes and negative surface charge in a lab-on-a-chip human blood-brain barrier model.

Santa-Maria AR, Walter FR, Figueiredo R, Kincses A, ... Dér A, Deli MA
Microfluidic lab-on-a-chip (LOC) devices allow the study of blood-brain barrier (BBB) properties in dynamic conditions. We studied a BBB model, consisting of human endothelial cells derived from hematopoietic stem cells in co-culture with brain pericytes, in an LOC device to study fluid flow in the regulation of endothelial, BBB and glycocalyx-related genes and surface charge. The highly negatively charged endothelial surface glycocalyx functions as mechano-sensor detecting shear forces generated by blood flow on the luminal side of brain endothelial cells and contributes to the physical barrier of the BBB. Despite the importance of glycocalyx in the regulation of BBB permeability in physiological conditions and in diseases, the underlying mechanisms remained unclear. The MACE-seq gene expression profiling analysis showed differentially expressed endothelial, BBB and glycocalyx core protein genes after fluid flow, as well as enriched pathways for the extracellular matrix molecules. We observed increased barrier properties, a higher intensity glycocalyx staining and a more negative surface charge of human brain-like endothelial cells (BLECs) in dynamic conditions. Our work is the first study to provide data on BBB properties and glycocalyx of BLECs in an LOC device under dynamic conditions and confirms the importance of fluid flow for BBB culture models.



J Cereb Blood Flow Metab: 08 Feb 2021:271678X21992638; epub ahead of print
Santa-Maria AR, Walter FR, Figueiredo R, Kincses A, ... Dér A, Deli MA
J Cereb Blood Flow Metab: 08 Feb 2021:271678X21992638; epub ahead of print | PMID: 33563079
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Abstract

Metabolomic and transcriptional profiling reveals bioenergetic stress and activation of cell death and inflammatory pathways after neuronal deletion of NAMPT.

Lundt S, Zhang N, Li JL, Zhang Z, ... Ge WP, Ding S
Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the NAD+ salvage pathway. Our previous study demonstrated that deletion of NAMPT gene in projection neurons using Thy1-NAMPT-/- conditional knockout (cKO) mice causes neuronal degeneration, muscle atrophy, neuromuscular junction abnormalities, paralysis and eventually death. Here we conducted a combined metabolomic and transcriptional profiling study in vivo in an attempt to further investigate the mechanism of neuronal degeneration at metabolite and mRNA levels after NAMPT deletion. Here using steady-state metabolomics, we demonstrate that deletion of NAMPT causes a significant decrease of NAD+ metabolome and bioenergetics, a buildup of metabolic intermediates upstream of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) in glycolysis, and an increase of oxidative stress. RNA-seq shows that NAMPT deletion leads to the increase of mRNA levels of enzymes in NAD metabolism, in particular PARP family of NAD+ consumption enzymes, as well as glycolytic genes Glut1, Hk2 and PFBFK3 before GAPDH. GO, KEGG and GSEA analyses show the activations of apoptosis, inflammation and immune responsive pathways and the inhibition of neuronal/synaptic function in the cKO mice. The current study suggests that increased oxidative stress, apoptosis and neuroinflammation contribute to neurodegeneration and mouse death as a direct consequence of bioenergetic stress after NAMPT deletion.



J Cereb Blood Flow Metab: 08 Feb 2021:271678X21992625; epub ahead of print
Lundt S, Zhang N, Li JL, Zhang Z, ... Ge WP, Ding S
J Cereb Blood Flow Metab: 08 Feb 2021:271678X21992625; epub ahead of print | PMID: 33563078
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Abstract

Lenticulostriate artery combined with neuroimaging markers of cerebral small vessel disease differentiate the pathogenesis of recent subcortical infarction.

Jiang S, Cao T, Yan Y, Yang T, ... Anderson CS, Wu B
Recent subcortical infarction (RSI) in the lenticulostriate artery (LSA) territory with a non-stenotic middle cerebral artery is a heterogeneous entity. We aimed to investigate the role of LSA combined with neuroimaging markers of cerebral small vessel disease (CSVD) in differentiating the pathogenic subtypes of RSI by whole-brain vessel-wall magnetic resonance imaging (WB-VWI). Fifty-two RSI patients without relevant middle cerebral artery (MCA) stenosis on magnetic resonance angiography were prospectively enrolled. RSI was dichotomized as branch atheromatous disease (BAD; a culprit plaque located adjacent to the LSA origin) (n = 34) and CSVD-related lacunar infarction (CSVD-related LI; without plaque or plaque located distal to the LSA origin) (n = 18). Logistic regression analysis showed lacunes (odds ratio [OR] 9.68, 95% confidence interval [CI] 1.71-54.72; P = 0.010) and smaller number of LSA branches (OR 0.59, 95% CI 0.36-0.96; P = 0.034) were associated with of BAD, whereas severe deep white matter hyperintensities (DWMH) (OR 0.11, 95% CI 0.02-0.71; P = 0.021) was associated with CSVD-related LI. In conclusion, the LSA branches combined with lacunes and severe DWMH may delineate subtypes of SSI. The WB-VWI technique could be a credible tool for delineating the heterogeneous entity of SSI in the LSA territory.



J Cereb Blood Flow Metab: 08 Feb 2021:271678X21992622; epub ahead of print
Jiang S, Cao T, Yan Y, Yang T, ... Anderson CS, Wu B
J Cereb Blood Flow Metab: 08 Feb 2021:271678X21992622; epub ahead of print | PMID: 33563077
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