Journal: J Cereb Blood Flow Metab

Sorted by: date / impact
Abstract

Deep medullary veins are associated with widespread brain structural abnormalities.

Liu ZY, Zhai FF, Ao DH, Han F, ... Jin ZY, Zhu YC
Our aim is to investigate the association of cerebral deep medullary veins (DMVs) with white matter microstructural integrity and regional brain atrophy in MRI. In a community-based cohort of 979 participants (mean age 55.4 years), DMVs were identified on susceptibility-weighted imaging. Brain structural measurements including gray matter and hippocampus volumes, as well as diffusion tensor metrics, were evaluated. The mean (SD)number of DMVs was 19.0 (1.7). A fewer number of DMVs was related to lower fractional anisotropy and higher mean diffusivity in multiple voxels on the white matter skeleton (threshold-free cluster enhancement corrected p < 0.05, adjusted for age and sex). Also, fewer DMVs were significantly related to a lower gray matter fraction and a hippocampal fraction (0.10 and 0.11 per DMV, respectively; SE, 0.03 for both; p < 0.001 for both). A significant correlation between DMVs\' reduction and cortical atrophy was observed in the bilateral occipital lobes, temporal lobes, hippocampus, and frontal lobes (p < 0.001, adjusted for age, sex, and total intracranial volume). Our results provided evidence that cerebral small venules disease play a role in brain parenchymal lesions and neurodegenerative processes.



J Cereb Blood Flow Metab: 01 Jun 2022; 42:997-1006
Liu ZY, Zhai FF, Ao DH, Han F, ... Jin ZY, Zhu YC
J Cereb Blood Flow Metab: 01 Jun 2022; 42:997-1006 | PMID: 34855528
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

RAGE-mediated T cell metabolic reprogramming shapes T cell inflammatory response after stroke.

Zhang Y, Li F, Chen C, Li Y, ... Wan J, Li P
The metabolic reprogramming of peripheral CD4+ T cells that occurs after stroke can lead to imbalanced differentiation of CD4+ T cells, including regulation of T cells, and presents a promising target for poststroke immunotherapy. However, the regulatory mechanism underlying the metabolic reprogramming of peripheral CD4+ T cell remains unknown. In this study, using combined transcription and metabolomics analyses, flow cytometry, and conditional knockout mice, we demonstrate that the receptor for advanced glycation end products (RAGE) can relay the ischemic signal to CD4+ T cells, which underwent acetyl coenzyme A carboxylase 1(ACC1)-dependent metabolic reprogramming after stroke. Furthermore, by administering soluble RAGE (sRAGE) after stroke, we demonstrate that neutralization of RAGE reversed the enhanced fatty acid synthesis of CD4+ T cells and the post-stroke imbalance of Treg/Th17. Finally, we found that post-stroke sRAGE treatment protected against infarct volume and ameliorated functional recovery. In conclusion, sRAGE can serve as a novel immunometabolic modulator that ameliorates ischemic stroke recovery by inhibiting fatty acid synthesis and thus favoring CD4+ T cells polarization toward Treg after cerebral ischemia injury. The above findings provide new insights for the treatment of neuroinflammatory responses after ischemia stroke.



J Cereb Blood Flow Metab: 01 Jun 2022; 42:952-965
Zhang Y, Li F, Chen C, Li Y, ... Wan J, Li P
J Cereb Blood Flow Metab: 01 Jun 2022; 42:952-965 | PMID: 34910890
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Systematic validation of structural brain networks in cerebral small vessel disease.

Dewenter A, Gesierich B, Ter Telgte A, Wiegertjes K, ... Tuladhar AM, Duering M
Cerebral small vessel disease (SVD) is considered a disconnection syndrome, which can be quantified using structural brain network analysis obtained from diffusion MRI. Network analysis is a demanding analysis approach and the added benefit over simpler diffusion MRI analysis is largely unexplored in SVD. In this pre-registered study, we assessed the clinical and technical validity of network analysis in two non-overlapping samples of SVD patients from the RUN DMC study (n = 52 for exploration and longitudinal analysis and n = 105 for validation). We compared two connectome pipelines utilizing single-shell or multi-shell diffusion MRI, while also systematically comparing different node and edge definitions. For clinical validation, we assessed the added benefit of network analysis in explaining processing speed and in detecting short-term disease progression. For technical validation, we determined test-retest repeatability.Our findings in clinical validation show that structural brain networks provide only a small added benefit over simpler global white matter diffusion metrics and do not capture short-term disease progression. Test-retest reliability was excellent for most brain networks. Our findings question the added value of brain network analysis in clinical applications in SVD and highlight the utility of simpler diffusion MRI based markers.



J Cereb Blood Flow Metab: 01 Jun 2022; 42:1020-1032
Dewenter A, Gesierich B, Ter Telgte A, Wiegertjes K, ... Tuladhar AM, Duering M
J Cereb Blood Flow Metab: 01 Jun 2022; 42:1020-1032 | PMID: 34929104
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Cerebrovascular reactivity and deep white matter hyperintensities in migraine: A prospective CO targeting study.

Lee MJ, Park BY, Cho S, Kim S, ... Kim ST, Chung CS
Several studies suggested the association of migraine with deep white matter hyperintensities (WMHs). We aimed to explore the cerebrovascular reactivity (CVR), deep WMH burden, and their association in patients with migraine using a state-of-the-art methodology. A total of 31 patients with migraine without aura and 31 age/sex-matched controls underwent 3T MRI with prospective end-tidal carbon dioxide (CO2) targeting. We quantified deep WMH clusters using an automated segmentation tool and measured voxel-wise CVR by changes in blood oxygen level-dependent signal fitted to subjects\' end-tidal CO2. The association of migraine and CVR with the presence of WMH in each voxel and interaction of migraine and CVR on WMH were analysed. Patients had a higher number of deep WMHs than controls (p = 0.015). Migraine and reduced CVR were associated with increased probability of having WMHs in each voxel (adjusted OR 30.78 [95% CI 1.89-500.53], p = 0.016 and adjusted OR 0.30 [0.29-0.32], p < 0.001, respectively). Migraine had an effect modification on CVR on deep WMHs (p for interaction <0.001): i.e. the association between CVR and WMH was greater in patients than in controls. We suggest that the migraine-WMH association can be explained by the effect modification on the CVR.



J Cereb Blood Flow Metab: 24 May 2022:271678X221103006; epub ahead of print
Lee MJ, Park BY, Cho S, Kim S, ... Kim ST, Chung CS
J Cereb Blood Flow Metab: 24 May 2022:271678X221103006; epub ahead of print | PMID: 35607990
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Global changes in diffusion tensor imaging during acute ischemic stroke and post-stroke cognitive performance.

Kern KC, Wright CB, Leigh R
Post-stroke cognitive impairment is related to the effects of the acute stroke and pre-stroke brain health. We tested whether diffusion tensor imaging (DTI) can detect acute, global effects of stroke and predict post-stroke cognitive performance. Patients with stroke or TIA enrolled in a prospective cohort study were included if they had 1) at least one DTI acquisition at acute presentation, 24 hours, 5 days, or 30 days, and 2) follow-up testing with the telephone Montreal Cognitive Assessment (T-MoCA) at 30 and/or 90 days. A whole brain, white-matter skeleton excluding the infarct was used to derive mean global DTI measures for mean diffusivity (MD), fractional anisotropy (FA), free water (FW), FW-corrected MD (MDtissue), and FW-corrected FA (FAtissue). In 74 patients with ischemic stroke or TIA, there was a transient 4.2% increase in mean global FW between acute presentation and 24 hours (p = 0.024) that returned to initial values by 30 days (p = 0.03). Each acute global DTI measure was associated with 30-day T-MoCA score (n = 61, p = 0.0011-0.0076). Acute global FW, MD, FA and FAtissue were also associated with 90-day T-MoCA (n = 56, p = 0.0034-0.049). Transient global FW elevation likely reflects stroke-related interstitial edema, whereas other global DTI measures are more representative of pre-stroke brain health.



J Cereb Blood Flow Metab: 17 May 2022:271678X221101644; epub ahead of print
Kern KC, Wright CB, Leigh R
J Cereb Blood Flow Metab: 17 May 2022:271678X221101644; epub ahead of print | PMID: 35579236
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Post-mortem correlates of Virchow-Robin spaces detected on MRI.

Haider L, Hametner S, Endmayr V, Mangesius S, ... Barkhof F, Kasprian G
The purpose of our study is to quantify the extent to which Virchow-Robin spaces (VRS) detected on in vivo MRI are reproducible by post-mortem MRI.Double Echo Steady State 3T MRIs were acquired post-mortem in 49 double- and 32 single-hemispheric formalin-fixed brain sections from 12 patients, who underwent conventional diagnostic 1.5 or 3T MRI in median 22 days prior to death (25% to 75%: 12 to 134 days). The overlap of in vivo and post-mortem VRS segmentations was determined accounting for potential confounding factors.The reproducibility of VRS found on in vivo MRI by post-mortem MRI, in the supratentorial white matter was in median 80% (25% to 75%: 60 to 100). A lower reproducibility was present in the basal ganglia, with a median of 47% (25% to 75%: 30 to 50).VRS segmentations were histologically confirmed in one double hemispheric section.Overall, the majority of VRS found on in vivo MRI was stable throughout death and formalin fixation, emphasizing the translational potential of post-mortem VRS studies.



J Cereb Blood Flow Metab: 17 May 2022:271678X211067455; epub ahead of print
Haider L, Hametner S, Endmayr V, Mangesius S, ... Barkhof F, Kasprian G
J Cereb Blood Flow Metab: 17 May 2022:271678X211067455; epub ahead of print | PMID: 35581687
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Increased interictal synchronicity of respiratory related brain pulsations in epilepsy.

Kananen J, Järvelä M, Korhonen V, Tuovinen T, ... LeVan P, Kiviniemi V
Respiratory brain pulsations have recently been shown to drive electrophysiological brain activity in patients with epilepsy. Furthermore, functional neuroimaging indicates that respiratory brain pulsations have increased variability and amplitude in patients with epilepsy compared to healthy individuals. To determine whether the respiratory drive is altered in epilepsy, we compared respiratory brain pulsation synchronicity between healthy controls and patients. Whole brain fast functional magnetic resonance imaging was performed on 40 medicated patients with focal epilepsy, 20 drug-naïve patients and 102 healthy controls. Cerebrospinal fluid associated respiratory pulsations were used to generate individual whole brain respiratory synchronization maps, which were compared between groups. Finally, we analyzed the seizure frequency effect and diagnostic accuracy of the respiratory synchronization defect in epilepsy. Respiratory brain pulsations related to the verified fourth ventricle pulsations were significantly more synchronous in patients in frontal, periventricular and mid-temporal regions, while the seizure frequency correlated positively with synchronicity. The respiratory brain synchronicity had a good diagnostic accuracy (ROCAUC = 0.75) in discriminating controls from medicated patients. The elevated respiratory brain synchronicity in focal epilepsy suggests altered physiological effect of cerebrospinal fluid pulsations possibly linked to regional brain water dynamics involved with interictal brain physiology.



J Cereb Blood Flow Metab: 14 May 2022:271678X221099703; epub ahead of print
Kananen J, Järvelä M, Korhonen V, Tuovinen T, ... LeVan P, Kiviniemi V
J Cereb Blood Flow Metab: 14 May 2022:271678X221099703; epub ahead of print | PMID: 35570730
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Validation, kinetic modeling, and test-retest reproducibility of [F]SynVesT-1 for PET imaging of synaptic vesicle glycoprotein 2A in mice.

Bertoglio D, Zajicek F, Lombaerde S, Miranda A, ... Verhaeghe J, Staelens S
Alterations in synaptic vesicle glycoprotein 2 A (SV2A) have been associated with several neuropsychiatric and neurodegenerative disorders. Therefore, SV2A positron emission tomography (PET) imaging may provide a unique tool to investigate synaptic density dynamics during disease progression and after therapeutic intervention. This study aims to extensively characterize the novel radioligand [18F]SynVesT-1 for preclinical applications. In C57Bl/6J mice (n = 39), we assessed the plasma profile of [18F]SynVesT-1, validated the use of a noninvasive image-derived input function (IDIF) compared to an arterial input function (AIF), performed a blocking study with levetiracetam (50 and 200 mg/kg, i.p.) to verify the specificity towards SV2A, examined kinetic models for volume of distribution (VT) quantification, and explored test-retest reproducibility of [18F]SynVesT-1 in the central nervous system (CNS). Plasma availability of [18F]SynVesT-1 decreased rapidly (13.4 ± 1.5% at 30 min post-injection). VT based on AIF and IDIF showed excellent agreement (r2 = 0.95, p < 0.0001) and could be reliably estimated with a 60-min acquisition. The blocking study resulted in a complete blockade with no suitable reference region. Test-retest analysis indicated good reproducibility (mean absolute variability <10%). In conclusion, [18F]SynVesT-1 is selective for SV2A with optimal kinetics representing a candidate tool to quantify CNS synaptic density non-invasively.



J Cereb Blood Flow Metab: 14 May 2022:271678X221101648; epub ahead of print
Bertoglio D, Zajicek F, Lombaerde S, Miranda A, ... Verhaeghe J, Staelens S
J Cereb Blood Flow Metab: 14 May 2022:271678X221101648; epub ahead of print | PMID: 35570828
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

: Transfer function analysis of dynamic cerebral autoregulation: To band or not to band?

Liu J, Simpson DM, Panerai RB
Transfer function analysis (TFA) is the most frequently adopted method for assessing dynamic cerebral autoregulation (CA) with continuously recorded arterial blood pressure (ABP) and cerebral blood flow velocity (CBFV). Conventionally, values of autoregulatory metrics (e.g., gain and phase) derived from TFA are averaged within three frequency bands separated by cut-off frequencies at 0.07 Hz and 0.20 Hz, respectively, to represent the efficiency of dynamic CA. However, this is of increasing concerns, as there remains no solid evidence for choosing these specific cut-off frequencies, and the rigid adoption of these bands can stifle further developments in TFA of dynamic CA. In this \'Point-Counterpoint\' mini-review, we provide evidence against the fixed banding, indicate possible alternatives, and call for awareness of the risk of the \'one-size-fits-all\' banding becoming dogmatic. We conclude that we need to remain open to the multiple possibilities offered by TFA to realize its full potential in studies of human dynamic CA.



J Cereb Blood Flow Metab: 05 May 2022:271678X221098448; epub ahead of print
Liu J, Simpson DM, Panerai RB
J Cereb Blood Flow Metab: 05 May 2022:271678X221098448; epub ahead of print | PMID: 35510667
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Intracerebral hemorrhage and thrombin-induced alterations in cerebral microvessel matrix.

Gu YH, Hawkins BT, Izawa Y, Yoshikawa Y, Koziol JA, Del Zoppo GJ
Four phase III clinical trials of oral direct factor Xa or thrombin inhibitors demonstrated significantly lower intracranial hemorrhage compared to warfarin in patients with nonvalvular-atrial fibrillation. This is counter-intuitive to the principle that inhibiting thrombosis should increase hemorrhagic risk. We tested the novel hypothesis that anti-thrombin activity decreases the risk of intracerebral hemorrhage by directly inhibiting thrombin-mediated degradation of cerebral microvessel basal lamina matrix, responsible for preventing hemorrhage. Collagen IV, laminin, and perlecan each contain one or more copies of the unique α-thrombin cleavage site consensus sequence. In blinded controlled experiments, α-thrombin significantly degraded each matrix protein in vitro and in vivo in a concentration-dependent fashion. In vivo stereotaxic injection of α-thrombin significantly increased permeability, local IgG extravasation, and hemoglobin (Hgb) deposition together with microvessel matrix degradation in a mouse model. In all formats the direct anti-thrombin dabigatran completely inhibited matrix degradation by α-thrombin. Fourteen-day oral exposure to dabigatran etexilate-containing chow completely inhibited matrix degradation, the permeability to large molecules, and cerebral hemorrhage associated with α-thrombin. These experiments demonstrate that thrombin can degrade microvessel matrix, leading to hemorrhage, and that inhibition of microvessel matrix degradation by α-thrombin decreases cerebral hemorrhage. Implications for focal ischemia and other conditions are discussed.



J Cereb Blood Flow Metab: 05 May 2022:271678X221099092; epub ahead of print
Gu YH, Hawkins BT, Izawa Y, Yoshikawa Y, Koziol JA, Del Zoppo GJ
J Cereb Blood Flow Metab: 05 May 2022:271678X221099092; epub ahead of print | PMID: 35510668
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Temporal brain transcriptome analysis reveals key pathological events after germinal matrix hemorrhage in neonatal rats.

Song J, Nilsson G, Xu Y, Zelco A, ... Zhu C, Wang X
Germinal matrix hemorrhage (GMH) is a common complication in preterm infants and is associated with high risk of adverse neurodevelopmental outcomes. We used a rat GMH model and performed RNA sequencing to investigate the signaling pathways and biological processes following hemorrhage. GMH induced brain injury characterized by early hematoma and subsequent tissue loss. At 6 hours after GMH, gene expression indicated an increase in mitochondrial activity such as ATP metabolism and oxidative phosphorylation along with upregulation of cytoprotective pathways and heme metabolism. At 24 hours after GMH, the expression pattern suggested an increase in cell cycle progression and downregulation of neurodevelopmental-related pathways. At 72 hours after GMH, there was an increase in genes related to inflammation and an upregulation of ferroptosis. Hemoglobin components and genes related to heme metabolism and ferroptosis such as Hmox1, Alox15, and Alas2 were among the most upregulated genes. We observed dysregulation of processes involved in development, mitochondrial function, cholesterol biosynthesis, and inflammation, all of which contribute to neurodevelopmental deterioration following GMH. This study is the first temporal transcriptome profile providing a comprehensive overview of the molecular mechanisms underlying brain injury following GMH, and it provides useful guidance in the search for therapeutic interventions.



J Cereb Blood Flow Metab: 01 May 2022:271678X221098811; epub ahead of print
Song J, Nilsson G, Xu Y, Zelco A, ... Zhu C, Wang X
J Cereb Blood Flow Metab: 01 May 2022:271678X221098811; epub ahead of print | PMID: 35491813
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Microglial phagocytosis and regulatory mechanisms after stroke.

Chen W, Zhang Y, Zhai X, Xie L, ... Wan J, Li P
Stroke, including ischemic stroke and hemorrhagic stroke can cause massive neuronal death and disruption of brain structure, which is followed by secondary inflammatory injury initiated by pro-inflammatory molecules and cellular debris. Phagocytic clearance of cellular debris by microglia, the brain\'s scavenger cells, is pivotal for neuroinflammation resolution and neurorestoration. However, microglia can also exacerbate neuronal loss by phagocytosing stressed-but-viable neurons in the penumbra, thereby expanding the injury area and hindering neurofunctional recovery. Microglia constantly patrol the central nervous system using their processes to scour the cellular environment and start or cease the phagocytosis progress depending on the \"eat me\" or \"don\'t eat me\'\' signals on cellular surface. An optimal immune response requires a delicate balance between different phenotypic states to regulate neuro-inflammation and facilitate reconstruction after stroke. Here, we examine the literature and discuss the molecular mechanisms and cellular pathways regulating microglial phagocytosis, their resulting effects in brain injury and neural regeneration, as well as the potential therapeutic targets that might modulate microglial phagocytic activity to improve neurological function after stroke.



J Cereb Blood Flow Metab: 01 May 2022:271678X221098841; epub ahead of print
Chen W, Zhang Y, Zhai X, Xie L, ... Wan J, Li P
J Cereb Blood Flow Metab: 01 May 2022:271678X221098841; epub ahead of print | PMID: 35491825
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Defining cerebral leukocyte populations in local ischemic blood samples from patients with hyperacute stroke.

Zimmermann L, Pham M, März AG, Kollikowski AM, Stoll G, Schuhmann MK
In acute stroke, neuroinflammation can nowadays be analyzed by local cerebral aspiration of pial-ischemic blood during mechanical thrombectomy. Recently, Shaw et al. reported on differences in leukocyte subpopulations within the occluded cerebrovascular compartment. In their study, a main proportion of granulocytes was lost during isolation. By immediate analysis, we found a reproducible increase in absolute local granulocytes without variations in absolute lymphocyte and monocyte numbers. Flow-cytometric phenotyping confirmed a high proportion of granulocytes and a local shift towards CD4+ T cells. Thus, immediate analysis appears to be critical to observe distinct local responses of leukocytes to acute ischemic stroke.



J Cereb Blood Flow Metab: 30 Apr 2022; 42:901-904
Zimmermann L, Pham M, März AG, Kollikowski AM, Stoll G, Schuhmann MK
J Cereb Blood Flow Metab: 30 Apr 2022; 42:901-904 | PMID: 35107055
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

The meningeal lymphatic vessels and the glymphatic system: Potential therapeutic targets in neurological disorders.

Li G, Cao Y, Tang X, Huang J, Cai L, Zhou L
The recent discovery of the meningeal lymphatic vessels (mLVs) and glymphatic pathways has challenged the long-lasting dogma that the central nervous system (CNS) lacks a lymphatic system and therefore does not interact with peripheral immunity. This discovery has reshaped our understanding of mechanisms underlying CNS drainage. Under normal conditions, a close connection between mLVs and the glymphatic system enables metabolic waste removal, immune cell trafficking, and CNS immune surveillance. Dysfunction of the glymphatic-mLV system can lead to toxic protein accumulation in the brain, and it contributes to the development of a series of neurodegenerative disorders, such as Alzheimer\'s and Parkinson\'s diseases. The identification of precise cerebral transport routes is based mainly on indirect, invasive imaging of animals, and the results cannot always be applied to humans. Here we review the functions of the glymphatic-mLV system and evidence for its involvement in some CNS diseases. We focus on emerging noninvasive imaging techniques to evaluate the human glymphatic-mLV system and their potential for preclinical diagnosis and prevention of neurodegenerative diseases. Potential strategies that target the glymphatic-mLV system in order to treat and prevent neurological disorders are also discussed.



J Cereb Blood Flow Metab: 28 Apr 2022:271678X221098145; epub ahead of print
Li G, Cao Y, Tang X, Huang J, Cai L, Zhou L
J Cereb Blood Flow Metab: 28 Apr 2022:271678X221098145; epub ahead of print | PMID: 35484910
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Early disturbance of dynamic synchronization and neurovascular coupling in cognitively normal Parkinson\'s disease.

Shang S, Ye J, Wu J, Zhang H, ... Chen YC, Yin X
Pathological process in Parkinson\'s disease (PD) is accompanied with functional and metabolic alterations. The time-varying properties of functional coherence and their coupling to regional perfusion are still rarely elucidated. To investigate early disruption of dynamic regional homogeneity (dReho) and neurovascular coupling in cognitively normal PD patients, dynamic neuronal synchronization and regional perfusion were measured using dReho and cerebral blood flow (CBF), respectively. Neurovascular coupling was assessed by CBF-ReHo correlation coefficient and CBF/ReHo ratio. Multivariate pattern analysis was conducted for the differentiating ability of each feature. Relative to healthy controls (HC) subjects, PD patients demonstrated increased dReho in middle temporal gyrus (MTG), rectus gyrus, middle occipital gyrus, and precuneus, whereas reduced dReho in putamen and supplementary motor area (SMA); while higher CBF/dReho ratio was located in putamen, SMA, paracentral lobule, and postcentral gyrus, whereas lower CBF/dReho ratio in superior temporal gyrus, MTG, precuneus, and angular gyrus (AG). Global and regional CBF-Reho decoupling were both observed in PD groups. The CBF/Reho ratio features achieved more powerful classification performance than other features. From the view of dynamic neural synchronization and neurovascular coupling, this study reinforced the insights into neural basis underlying PD and the potential role in the disease diagnosis and differentiation.



J Cereb Blood Flow Metab: 26 Apr 2022:271678X221098503; epub ahead of print
Shang S, Ye J, Wu J, Zhang H, ... Chen YC, Yin X
J Cereb Blood Flow Metab: 26 Apr 2022:271678X221098503; epub ahead of print | PMID: 35473430
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

The lateral entorhinal cortex is a hub for local and global dysfunction in early Alzheimer\'s disease states.

Mandino F, Yeow LY, Bi R, Sejin L, ... Gigg J, Grandjean J
Functional network activity alterations are one of the earliest hallmarks of Alzheimer\'s disease (AD), detected prior to amyloidosis and tauopathy. Better understanding the neuronal underpinnings of such network alterations could offer mechanistic insight into AD progression. Here, we examined a mouse model (3xTgAD mice) recapitulating this early AD stage. We found resting functional connectivity loss within ventral networks, including the entorhinal cortex, aligning with the spatial distribution of tauopathy reported in humans. Unexpectedly, in contrast to decreased connectivity at rest, 3xTgAD mice show enhanced fMRI signal within several projection areas following optogenetic activation of the entorhinal cortex. We corroborate this finding by demonstrating neuronal facilitation within ventral networks and synaptic hyperexcitability in projection targets. 3xTgAD mice, thus, reveal a dichotomic hypo-connected:resting versus hyper-responsive:active phenotype. This strong homotopy between the areas affected supports the translatability of this pathophysiological model to tau-related, early-AD deficits in humans.



J Cereb Blood Flow Metab: 25 Apr 2022:271678X221082016; epub ahead of print
Mandino F, Yeow LY, Bi R, Sejin L, ... Gigg J, Grandjean J
J Cereb Blood Flow Metab: 25 Apr 2022:271678X221082016; epub ahead of print | PMID: 35466772
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Free-water diffusion MRI detects structural alterations surrounding white matter hyperintensities in the early stage of cerebral small vessel disease.

Mayer C, Nägele FL, Petersen M, Frey BM, ... Thomalla G, Cheng B
In cerebral small vessel disease (CSVD), both white matter hyperintensities (WMH) of presumed vascular origin and the normal-appearing white matter (NAWM) contain microstructural brain alterations on diffusion-weighted MRI (DWI). Contamination of DWI-derived metrics by extracellular free-water can be corrected with free-water (FW) imaging. We investigated the alterations in FW and FW-corrected fractional anisotropy (FA-t) in WMH and surrounding tissue and their association with cerebrovascular risk factors. We analysed 1,000 MRI datasets from the Hamburg City Health Study. DWI was used to generate FW and FA-t maps. WMH masks were segmented on FLAIR and T1-weighted MRI and dilated repeatedly to create 8 NAWM masks representing increasing distance from WMH. Linear models were applied to compare FW and FA-t across WMH and NAWM masks and in association with cerebrovascular risk. Median age was 64 ± 14 years. FW and FA-t were altered 8 mm and 12 mm beyond WMH, respectively. Smoking was significantly associated with FW in NAWM (p = 0.008) and FA-t in WMH (p = 0.008) and in NAWM (p = 0.003) while diabetes and hypertension were not. Further research is necessary to examine whether FW and FA-t alterations in NAWM are predictors for developing WMH.



J Cereb Blood Flow Metab: 11 Apr 2022:271678X221093579; epub ahead of print
Mayer C, Nägele FL, Petersen M, Frey BM, ... Thomalla G, Cheng B
J Cereb Blood Flow Metab: 11 Apr 2022:271678X221093579; epub ahead of print | PMID: 35410517
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Genetic ablation of smooth muscle K2.1 is inconsequential to the function of mouse cerebral arteries.

Kowalewska PM, Fletcher J, Jackson WF, Brett SE, ... Nelson MT, Welsh DG
Cerebral blood flow is a finely tuned process dependent on coordinated changes in arterial tone. These changes are strongly tied to smooth muscle membrane potential and inwardly rectifying K+ (KIR) channels are thought to be a key determinant. To elucidate the role of KIR2.1 in cerebral arterial tone development, this study examined the electrical and functional properties of cells, vessels and living tissue from tamoxifen-induced smooth muscle cell (SMC)-specific KIR2.1 knockout mice. Patch-clamp electrophysiology revealed a robust Ba2+-sensitive inwardly rectifying K+ current in cerebral arterial myocytes irrespective of KIR2.1 knockout. Immunolabeling clarified that KIR2.1 expression was low in SMCs while KIR2.2 labeling was remarkably abundant at the membrane. In alignment with these observations, pressure myography revealed that the myogenic response and K+-induced dilation were intact in cerebral arteries post knockout. At the whole organ level, this translated to a maintenance of brain perfusion in SMC KIR2.1-/- mice, as assessed with arterial spin-labeling MRI. We confirmed these findings in superior epigastric arteries and implicated KIR2.2 as more functionally relevant in SMCs. Together, these results suggest that subunits other than KIR2.1 play a significant role in setting native current in SMCs and driving arterial tone.



J Cereb Blood Flow Metab: 11 Apr 2022:271678X221093432; epub ahead of print
Kowalewska PM, Fletcher J, Jackson WF, Brett SE, ... Nelson MT, Welsh DG
J Cereb Blood Flow Metab: 11 Apr 2022:271678X221093432; epub ahead of print | PMID: 35410518
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Lower cerebral oxygen utilization is associated with Alzheimer\'s disease-related neurodegeneration and poorer cognitive performance among apolipoprotein E ε4 carriers.

Robb WH, Khan OA, Ahmed HA, Li J, ... Hohman TJ, Jefferson AL
Oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2) are markers of cerebral oxygen homeostasis and metabolism that may offer insights into abnormal changes in brain aging. The present study cross-sectionally related OEF and CMRO2 to cognitive performance and structural neuroimaging variables among older adults (n = 246, 74 ± 7 years, 37% female) and tested whether apolipoprotein E (APOE)-ε4 status modified these associations. Main effects of OEF and CMRO2 were null (p-values >0.06), and OEF interactions with APOE-ε4 status on cognitive and structural imaging outcomes were null (p-values >0.06). However, CMRO2 interacted with APOE-ε4 status on language (p = 0.002), executive function (p = 0.03), visuospatial (p = 0.005), and episodic memory performances (p = 0.03), and on hippocampal (p = 0.006) and inferior lateral ventricle volumes (p = 0.02). In stratified analyses, lower oxygen metabolism related to worse language (p = 0.02) and episodic memory performance (p = 0.03) among APOE-ε4 carriers only. Associations between CMRO2 and cognitive performance were primarily driven by APOE-ε4 carriers with existing cognitive impairment. Congruence across language and episodic memory results as well as hippocampal and inferior lateral ventricle volume findings suggest that APOE-ε4 may interact with cerebral oxygen metabolism in the pathogenesis of Alzheimer\'s disease and related neurodegeneration.



J Cereb Blood Flow Metab: 31 Mar 2022; 42:642-655
Robb WH, Khan OA, Ahmed HA, Li J, ... Hohman TJ, Jefferson AL
J Cereb Blood Flow Metab: 31 Mar 2022; 42:642-655 | PMID: 34743630
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Quantification of monoacylglycerol lipase and its occupancy by an exogenous ligand in rhesus monkey brains using [F]T-401 and PET.

Hattori Y, Seki C, Maeda J, Nagai Y, ... Koike T, Higuchi M
Monoacylglycerol lipase (MAGL) is a cytosolic serine hydrolase that cleaves monoacylglycerols into fatty acids and is a potential target for the novel treatment of CNS disorders related to the endocannabinoid system and neuroinflammation. We have developed [18F]T-401 as a selective Positron emission tomography (PET) imaging agent for MAGL. In this study, we determined an analytical method to quantify MAGL availability and its occupancy by an exogenous inhibitor in rhesus monkey brains using [18F]T-401-PET. In rhesus monkeys, regional time-activity curves were described well when using an extended 2-tissue compartment model that accommodated the formation of a radiometabolite in the brain. This model yielded reliable estimates of the total distribution volume (VT), and the rank order of VT was consistent with known regional activity of MAGL enzyme in primates. The pretreatment of monkeys with JW642 resulted in a dose-dependent reduction of [18F]T-401 retentions in the brain, and VT. Lassen\'s graphical analysis indicated a VND of 0.69 mL/cm3 and a plasma JW642 concentration of 126 ng/mL for inhibiting the specific binding by 50%. [18F]T-401 and the method established can be used for quantification of MAGL in healthy brain and in disease conditions, and is suitable for evaluations of target engagement at cerebral MAGL.



J Cereb Blood Flow Metab: 31 Mar 2022; 42:656-666
Hattori Y, Seki C, Maeda J, Nagai Y, ... Koike T, Higuchi M
J Cereb Blood Flow Metab: 31 Mar 2022; 42:656-666 | PMID: 34727758
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Arterial spin labeling demonstrates preserved regional cerebral blood flow in the P301L mouse model of tauopathy.

Kindler D, Maschio C, Ni R, Zerbi V, Razansky D, Klohs J
There is growing evidence for the vascular contribution to cognitive impairment and dementia in Alzheimer\'s disease (AD) and other neurodegenerative diseases. While perfusion deficits have been observed in patients with Alzheimer\'s disease and tauopaties, little is known about the role of tau in vascular dysfunction. In the present study, regional cerebral blood (rCBF) was characterized in P301L mice with arterial spin labeling. No differences in rCBF in P301L mice compared to their age-matched non-transgenic littermates at mid (10-12 months of age) and advanced (19-21 months of age) disease stages. This was concomitant with preservation of cortical brain structure as assessed with structural T2-weighted magnetic resonance imaging. These results show that hypoperfusion and neurodegeneration are not a phenotype of P301L mice. More studies are thus needed to understand the relationship of tau, neurodegeneration and vascular dysfunction and its modulators in AD and primary tauopathies.



J Cereb Blood Flow Metab: 31 Mar 2022; 42:686-693
Kindler D, Maschio C, Ni R, Zerbi V, Razansky D, Klohs J
J Cereb Blood Flow Metab: 31 Mar 2022; 42:686-693 | PMID: 34822744
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

A new perspective on cerebrospinal fluid dynamics after subarachnoid hemorrhage: From normal physiology to pathophysiological changes.

Fang Y, Huang L, Wang X, Si X, ... Zhang J, Zhang JH
Knowledge about the dynamic metabolism and function of cerebrospinal fluid (CSF) physiology has rapidly progressed in recent decades. It has traditionally been suggested that CSF is produced by the choroid plexus and drains to the arachnoid villi. However, recent findings have revealed that the brain parenchyma produces a large portion of CSF and drains through the perivascular glymphatic system and meningeal lymphatic vessels into the blood. The primary function of CSF is not limited to maintaining physiological CNS homeostasis but also participates in clearing waste products resulting from neurodegenerative diseases and acute brain injury. Aneurysmal subarachnoid hemorrhage (SAH), a disastrous subtype of acute brain injury, is associated with high mortality and morbidity. Post-SAH complications contribute to the poor outcomes associated with SAH. Recently, abnormal CSF flow was suggested to play an essential role in the post-SAH pathophysiological changes, such as increased intracerebral pressure, brain edema formation, hydrocephalus, and delayed blood clearance. An in-depth understanding of CSF dynamics in post-SAH events would shed light on potential development of SAH treatment options. This review summarizes and updates the latest physiological characteristics of CSF dynamics and discusses potential pathophysiological changes and therapeutic targets after SAH.



J Cereb Blood Flow Metab: 31 Mar 2022; 42:543-558
Fang Y, Huang L, Wang X, Si X, ... Zhang J, Zhang JH
J Cereb Blood Flow Metab: 31 Mar 2022; 42:543-558 | PMID: 34806932
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Tissue-type plasminogen activator induces TNF-α-mediated preconditioning of the blood-brain barrier.

Diaz A, Woo Y, Martin-Jimenez C, Merino P, Torre E, Yepes M
Ischemic tolerance is a phenomenon whereby transient exposure to a non-injurious preconditioning stimulus triggers resistance to a subsequent lethal ischemic insult. Despite the fact that not only neurons but also astrocytes and endothelial cells have a unique response to preconditioning stimuli, current research has been focused mostly on the effect of preconditioning on neuronal death. Thus, it is unclear if the blood-brain barrier (BBB) can be preconditioned independently of an effect on neuronal survival. The release of tissue-type plasminogen activator (tPA) from perivascular astrocytes in response to an ischemic insult increases the permeability of the BBB. In line with these observations, treatment with recombinant tPA increases the permeability of the BBB and genetic deficiency of tPA attenuates the development of post-ischemic edema. Here we show that tPA induces ischemic tolerance in the BBB independently of an effect on neuronal survival. We found that tPA renders the BBB resistant to an ischemic injury by inducing TNF-α-mediated astrocytic activation and increasing the abundance of aquaporin-4-immunoreactive astrocytic end-feet processes in the neurovascular unit. This is a new role for tPA, that does not require plasmin generation, and with potential therapeutic implications for patients with cerebrovascular disease.



J Cereb Blood Flow Metab: 31 Mar 2022; 42:667-682
Diaz A, Woo Y, Martin-Jimenez C, Merino P, Torre E, Yepes M
J Cereb Blood Flow Metab: 31 Mar 2022; 42:667-682 | PMID: 34796748
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

from diffusion MRI reveals a correspondence between ventricular cerebrospinal fluid volume and flow in the ischemic rodent model.

Jang M, Han S, Cho H
Quantitative measurement of cerebrospinal fluid (CSF) flow and volume and longitudinal monitoring of CSF dynamics provide insights into the compensatory characteristics of post-stroke CSF. In this study, we compared the MRI pseudo-diffusion index (D*) of live and sacrificed rat brains to confirm the effect of ventricular CSF flow on diffusion signals. We observed the relationship between the CSF peak velocities and D* through Monte Carlo (MC) simulations to further understand the source of D* contrast. We also determined the dominant CSF flow using D* in three directions. Finally, we investigated the dynamic evolutions of ventricular CSF flow and volume in a stroke rat model (n = 8) from preoperative to up to 45 days after surgery and determined the correlation between ventricular CSF volume and flow. MC simulations showed a strong positive correlation between the CSF peak velocity and D* (r = 0.99). The dominant CSF flow variations in the 3D ventricle could be measured using the maximum D* map. A longitudinal positive correlation between ventricular CSF volume and D* was observed in the lateral (r = 0.74) and ventral-third (r = 0.81) ventricles, respectively. The directional D* measurements provide quantitative CSF volume and flow information, which would provide useful insights into ischemic stroke with diffusion MRI.



J Cereb Blood Flow Metab: 31 Mar 2022; 42:572-583
Jang M, Han S, Cho H
J Cereb Blood Flow Metab: 31 Mar 2022; 42:572-583 | PMID: 34796772
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Serotonin 1B receptor density mapping of the human brainstem using positron emission tomography and autoradiography.

Veldman ER, Varrone A, Varnäs K, Svedberg MM, ... Halldin C, Lundberg J
The serotonin 1B (5-HT1B) receptor has lately received considerable interest in relation to psychiatric and neurological diseases, partly due to findings based on quantification using Positron Emission Tomography (PET). Although the brainstem is an important structure in this regard, PET radioligand binding quantification in brainstem areas often shows poor reliability. This study aims to improve PET quantification of 5-HT1B receptor binding in the brainstem.Volumes of interest (VOIs) were selected based on a 3D [3H]AZ10419369 Autoradiography brainstem model, which visualized 5-HT1B receptor distribution in high resolution. Two previously developed VOI delineation methods were tested and compared to a conventional manual method. For a method based on template data, a [11C]AZ10419369 PET template was created by averaging parametric binding potential (BPND) images of 52 healthy subjects. VOIs were generated based on a predefined volume and BPND thresholding and subsequently applied to test-retest [11C]AZ10419369 parametric BPND images of 8 healthy subjects. For a method based on individual subject data, VOIs were generated directly on each individual parametric image.Both methods showed improved reliability compared to a conventional manual VOI. The VOIs created with [11C]AZ10419369 template data can be automatically applied to future PET studies measuring 5-HT1B receptor binding in the brainstem.



J Cereb Blood Flow Metab: 31 Mar 2022; 42:630-641
Veldman ER, Varrone A, Varnäs K, Svedberg MM, ... Halldin C, Lundberg J
J Cereb Blood Flow Metab: 31 Mar 2022; 42:630-641 | PMID: 34644198
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Targeting maintains adult blood-brain barrier and central nervous system homeostasis.

Gueniot F, Rubin S, Bougaran P, Abelanet A, ... Couffinhal T, Duplàa C
Blood brain barrier (BBB) disruption is a critical component of the pathophysiology of cognitive impairment of vascular etiology (VCI) and associated with Alzheimer\'s disease (AD). The Wnt pathway plays a crucial role in BBB maintenance, but there is limited data on its role in cognitive pathologies. The E3 ubiquitin ligase PDZRN3 is a regulator of the Wnt pathway. In a murine model of VCI, overexpressing Pdzrn3 in endothelial cell (EC) exacerbated BBB hyperpermeability and accelerated cognitive decline. We extended these observations, in both VCI and AD models, showing that EC-specific depletion of Pdzrn3, reinforced the BBB, with a decrease in vascular permeability and a subsequent spare in cognitive decline. We found that in cerebral vessels, Pdzrn3 depletion protects against AD-induced Wnt target gene alterations and enhances endothelial tight junctional proteins. Our results provide evidence that Wnt signaling could be a molecular link regulating BBB integrity and cognitive decline under VCI and AD pathologies.



J Cereb Blood Flow Metab: 31 Mar 2022; 42:613-629
Gueniot F, Rubin S, Bougaran P, Abelanet A, ... Couffinhal T, Duplàa C
J Cereb Blood Flow Metab: 31 Mar 2022; 42:613-629 | PMID: 34644209
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Decreased rates of cerebral protein synthesis in conscious young adults with fragile X syndrome demonstrated by L-[1-C]leucine PET.

Schmidt KC, Loutaev I, Burlin TV, Thurm A, Sheeler C, Smith CB
Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. Fragile X mental retardation protein, a putative translation suppressor, is significantly reduced in FXS. The prevailing hypothesis is that rates of cerebral protein synthesis (rCPS) are increased by the absence of this regulatory protein. We have previously reported increased rCPS in the Fmr1 knockout mouse model of FXS. To address the hypothesis in human subjects, we measured rCPS in young men with FXS with L-[1-11C]leucine PET. In previous studies we had used sedation during imaging, and we did not find increases in rCPS as had been seen in the mouse model. Since mouse measurements were conducted in awake animals, we considered the possibility that sedation may have confounded our results. In the present study we used a modified and validated PET protocol that made it easier for participants with FXS to undergo the study awake. We compared rCPS in 10 fragile X participants and 16 healthy controls all studied while awake. Contrary to the prevailing hypothesis and findings in Fmr1 knockout mice, results indicate that rCPS in awake participants with FXS are decreased in whole brain and most brain regions by 13-21% compared to healthy controls.



J Cereb Blood Flow Metab: 29 Mar 2022:271678X221090997; epub ahead of print
Schmidt KC, Loutaev I, Burlin TV, Thurm A, Sheeler C, Smith CB
J Cereb Blood Flow Metab: 29 Mar 2022:271678X221090997; epub ahead of print | PMID: 35350914
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Altered glymphatic enhancement of cerebrospinal fluid tracer in individuals with chronic poor sleep quality.

Eide PK, Pripp AH, Berge B, Hrubos-Strøm H, Ringstad G, Valnes LM
Chronic sleep disturbance is a risk factor for dementia disease, possibly due to impaired sleep-dependent clearance of toxic metabolic by-products. We compared enrichment of a cerebrospinal fluid (CSF) tracer within brain of patients reporting good or poor sleep quality, assessed by the Pittsburgh Sleep Quality Index (PSQI) questionnaire. Tracer enrichment in a selection of brain regions was assessed using multiphase magnetic resonance imaging up to 48 hours after intrathecal administration of the contrast agent gadobutrol (0.5 ml of 1 mmol/ml) serving as tracer. Tracer enrichment differed between patients with good (PSQI ≤5) and poor (PSQI >5) sleep quality in a cohort of non-dementia individuals (n = 44; age 42.3 ± 14.5 years), and in patients with the dementia subtype idiopathic normal pressure hydrocephalus (n = 24; age 71.0 ± 4.9 years). Sleep impairment was associated with increased CSF tracer enrichment in several brain regions. Cortical brain volume as well as entorhinal cortex thickness was reduced in the oldest cohort and was correlated with the severity of sleep disturbance and the degree of cortical tracer enrichment. We suggest chronic sleep disturbance is accompanied by altered glymphatic function along enlarged perivascular spaces.



J Cereb Blood Flow Metab: 29 Mar 2022:271678X221090747; epub ahead of print
Eide PK, Pripp AH, Berge B, Hrubos-Strøm H, Ringstad G, Valnes LM
J Cereb Blood Flow Metab: 29 Mar 2022:271678X221090747; epub ahead of print | PMID: 35350917
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Altered resting-state cerebral blood flow and functional connectivity mediate suicidal ideation in major depressive disorder.

Fan D, He C, Liu X, Zang F, ... Zhang Z, Xie C
The relationships among cerebral blood flow (CBF), functional connectivity (FC) and suicidal ideation (SI) in major depressive disorder (MDD) patients have remained elusive. In this study, we characterized the changes in CBF and FC among 175 individuals including 47 MDD without SI (MDDNSI), 59 MDD with SI (MDDSI), and 69 healthy control (HC) who underwent arterial spin labeling and resting-state functional MRI scans. Then the voxel-wise CBF, seed-based FC and partial correlation analyses were measured. Mediation analysis was carried out to reveal the effects of FC on the association between CBF and behavioral performances in both subgroups. Results showed that CBF was higher in MDDSI patients in the bilateral precuneus compared to HC and MDDNSI participants. MDDSI patients exhibited enhanced FC in the prefrontal-limbic system and decreased FC in the sensorimotor cortex (SMC) relative to MDDNSI patients. CBF and FC were significantly correlated with clinical variables. More importantly, exploratory mediation analyses identified that abnormal FC can mediate the association between regional CBF and behavioral performances. These results highlight the potential role of precuneus gyrus, prefrontal-limbic system as well as SMC in the process of suicide and provide new insights into the neural mechanism underlying suicide in MDD patients.



J Cereb Blood Flow Metab: 29 Mar 2022:271678X221090998; epub ahead of print
Fan D, He C, Liu X, Zang F, ... Zhang Z, Xie C
J Cereb Blood Flow Metab: 29 Mar 2022:271678X221090998; epub ahead of print | PMID: 35350926
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

pH and proton-sensitive receptors in brain ischemia.

Zha XM, Xiong ZG, Simon RP
Extracellular proton concentration is at 40 nM when pH is 7.4. In disease conditions such as brain ischemia, proton concentration can reach µM range. To respond to this increase in extracellular proton concentration, the mammalian brain expresses at least three classes of proton receptors. Acid-sensing ion channels (ASICs) are the main neuronal cationic proton receptor. The proton-activated chloride channel (PAC), which is also known as (aka) acid-sensitive outwardly rectifying anion channel (ASOR; TMEM206), mediates acid-induced chloride currents. Besides proton-activated channels, GPR4, GPR65 (aka TDAG8, T-cell death-associated gene 8), and GPR68 (aka OGR1, ovarian cancer G protein-coupled receptor 1) function as proton-sensitive G protein-coupled receptors (GPCRs). Though earlier studies on these GPCRs mainly focus on peripheral cells, we and others have recently provided evidence for their functional importance in brain injury. Specifically, GPR4 shows strong expression in brain endothelium, GPR65 is present in a fraction of microglia, while GPR68 exhibits predominant expression in brain neurons. Here, to get a better view of brain acid signaling and its contribution to ischemic injury, we will review the recent findings regarding the differential contribution of proton-sensitive GPCRs to cerebrovascular function, neuroinflammation, and neuronal injury following acidosis and brain ischemia.



J Cereb Blood Flow Metab: 18 Mar 2022:271678X221089074; epub ahead of print
Zha XM, Xiong ZG, Simon RP
J Cereb Blood Flow Metab: 18 Mar 2022:271678X221089074; epub ahead of print | PMID: 35301897
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Choroid plexus function in neurological homeostasis and disorders: The awakening of the circadian clocks and orexins.

Christensen J, Li C, Mychasiuk R
As research regarding the role of circadian rhythms, sleep, and the orexinergic system in neurodegenerative diseases is growing, it is surprising that the choroid plexus (CP) remains underappreciated in this realm. Despite its extensive role in the regulation of circadian rhythms and orexinergic signalling, as well as acting as the primary conduit between cerebrospinal fluid (CSF) and the circulatory system, providing a mechanism by which toxic waste molecules can be removed from the brain, the CP has been largely unexplored in neurodegeneration. In this review, we explore the role of the CP in maintaining brain homeostasis and circadian rhythms, regulating CSF dynamics, and how these functions change across the lifespan, from development to senescence. In addition, we examine the relationship between the CP, orexinergic signalling, and the glymphatic system, highlighting gaps in the literature and areas that require immediate exploration. Finally, we assess current knowledge, including possible therapeutic strategies, regarding the role of the CP in neurological disorders, such as traumatic brain injury, migraine, Alzheimer\'s disease, and multiple sclerosis.



J Cereb Blood Flow Metab: 16 Mar 2022:271678X221082786; epub ahead of print
Christensen J, Li C, Mychasiuk R
J Cereb Blood Flow Metab: 16 Mar 2022:271678X221082786; epub ahead of print | PMID: 35296175
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Astrocyte regulation of cerebral blood flow during hypoglycemia.

Nippert AR, Chiang PP, Del Franco AP, Newman EA
Hypoglycemia triggers increases in cerebral blood flow (CBF), augmenting glucose supply to the brain. We have tested whether astrocytes, which can regulate vessel tone, contribute to this CBF increase. We hypothesized that hypoglycemia-induced adenosine signaling acts to increase astrocyte Ca2+ activity, which then causes the release of prostaglandins (PGs) and epoxyeicosatrienoic acids (EETs), leading to the dilation of brain arterioles and blood flow increases. We used an awake mouse model to investigate the effects of insulin-induced hypoglycemia on arterioles and astrocytes in the somatosensory cortex. During insulin-induced hypoglycemia, penetrating arterioles dilated and astrocyte Ca2+ signaling increased when blood glucose dropped below a threshold of ∼50 mg/dL. Application of the A2A adenosine receptor antagonist ZM-241385 eliminated hypoglycemia-evoked astrocyte Ca2+ increases and reduced arteriole dilations by 44% (p < 0.05). SC-560 and miconazole, which block the production of the astrocyte vasodilators PGs and EETs respectively, reduced arteriole dilations in response to hypoglycemia by 89% (p < 0.001) and 76% (p < 0.001). Hypoglycemia-induced arteriole dilations were decreased by 65% (p < 0.001) in IP3R2 knockout mice, which have reduced astrocyte Ca2+ signaling compared to wild-type. These results support the hypothesis that astrocytes contribute to hypoglycemia-induced increases in CBF by releasing vasodilators in a Ca2+-dependent manner.



J Cereb Blood Flow Metab: 16 Mar 2022:271678X221089091; epub ahead of print
Nippert AR, Chiang PP, Del Franco AP, Newman EA
J Cereb Blood Flow Metab: 16 Mar 2022:271678X221089091; epub ahead of print | PMID: 35296178
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Aging related impairment of brain microvascular bioenergetics involves oxidative phosphorylation and glycolytic pathways.

Sakamuri SS, Sure VN, Kolli L, Evans WR, ... Mostany R, Katakam PV
Mitochondrial and glycolytic energy pathways regulate the vascular functions. Aging impairs the cerebrovascular function and increases the risk of stroke and cognitive dysfunction. The goal of our study is to characterize the impact of aging on brain microvascular energetics. We measured the oxygen consumption and extracellular acidification rates of freshly isolated brain microvessels (BMVs) from young (2-4 months) and aged (20-22 months) C57Bl/6 male mice. Cellular ATP production in BMVs was predominantly dependent on oxidative phosphorylation (OXPHOS) with glucose as the preferred energy substrate. Aged BMVs exhibit lower ATP production rate with diminished OXPHOS and glycolytic rate accompanied by increased utilization of glutamine. Impairments of glycolysis displayed by aged BMVs included reduced compensatory glycolysis whereas impairments of mitochondrial respiration involved reduction of spare respiratory capacity and proton leak. Aged BMVs showed reduced levels of key glycolysis proteins including glucose transporter 1 and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 but normal lactate dehydrogenase activity. Mitochondrial protein levels were mostly unchanged whereas citrate synthase activity was reduced, and glutamate dehydrogenase was increased in aged BMVs. Thus, for the first time, we identified the dominant role of mitochondria in bioenergetics of BMVs and the alterations of the energy pathways that make the aged BMVs vulnerable to injury.



J Cereb Blood Flow Metab: 15 Mar 2022:271678X211069266; epub ahead of print
Sakamuri SS, Sure VN, Kolli L, Evans WR, ... Mostany R, Katakam PV
J Cereb Blood Flow Metab: 15 Mar 2022:271678X211069266; epub ahead of print | PMID: 35296173
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Mapping oxidative metabolism in the human brain with calibrated fMRI in health and disease.

Chen JJ, Uthayakumar B, Hyder F
Conventional functional MRI (fMRI) with blood-oxygenation level dependent (BOLD) contrast is an important tool for mapping human brain activity non-invasively. Recent interest in quantitative fMRI has renewed the importance of oxidative neuroenergetics as reflected by cerebral metabolic rate of oxygen consumption (CMRO2) to support brain function. Dynamic CMRO2 mapping by calibrated fMRI require multi-modal measurements of BOLD signal along with cerebral blood flow (CBF) and/or volume (CBV). In human subjects this \"calibration\" is typically performed using a gas mixture containing small amounts of carbon dioxide and/or oxygen-enriched medical air, which are thought to produce changes in CBF (and CBV) and BOLD signal with minimal or no CMRO2 changes. However non-human studies have demonstrated that the \"calibration\" can also be achieved without gases, revealing good agreement between CMRO2 changes and underlying neuronal activity (e.g., multi-unit activity and local field potential). Given the simpler set-up of gas-free calibrated fMRI, there is evidence of recent clinical applications for this less intrusive direction. This up-to-date review emphasizes technological advances for such translational gas-free calibrated fMRI experiments, also covering historical progression of the calibrated fMRI field that is impacting neurological and neurodegenerative investigations of the human brain.



J Cereb Blood Flow Metab: 15 Mar 2022:271678X221077338; epub ahead of print
Chen JJ, Uthayakumar B, Hyder F
J Cereb Blood Flow Metab: 15 Mar 2022:271678X221077338; epub ahead of print | PMID: 35296177
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Cerebrovascular responses to somatomotor stimulation in Parkinson\'s disease: A multivariate analysis.

Barnes SC, Panerai RB, Beishon L, Hanby M, Robinson TG, Haunton VJ
Parkinson\'s disease (PD) is a common neurodegenerative disorder, yet little is known about cerebral haemodynamics in this patient population. Previous studies assessing dynamic cerebral autoregulation (dCA), neurovascular coupling (NVC) and vasomotor reactivity (VMR) have yielded conflicting findings. By using multi-variate modelling, we aimed to determine whether cerebral blood flow (CBF) regulation is impaired in PD patients.55 healthy controls (HC) and 49 PD patients were recruited. PD subjects underwent a second recording following a period of abstinence from their anti-Parkinsonian medication. Continuous bilateral transcranial Doppler in the middle cerebral arteries, beat-to-beat mean arterial blood pressure (MAP; Finapres), heart rate (HR; electrocardiogram), and end-tidal CO2 (EtCO2; capnography) were measured. After a 5-min baseline period, a passive motor paradigm comprising 60 s of elbow flexion was performed. Multi-variate modelling quantified the contributions of MAP, ETCO2 and neural stimulation to changes in CBF velocity (CBFV). dCA, VMR and NVC were quantified to assess the integrity of CBF regulation.Neural stimulation was the dominant input. dCA, NVC and VMR were all found to be impaired in the PD population relative to HC (p < 0.01, p = 0.04, p < 0.01, respectively). Our data suggest PD may be associated with depressed CBF regulation. This warrants further assessment using different neural stimuli.



J Cereb Blood Flow Metab: 14 Mar 2022:271678X211065204; epub ahead of print
Barnes SC, Panerai RB, Beishon L, Hanby M, Robinson TG, Haunton VJ
J Cereb Blood Flow Metab: 14 Mar 2022:271678X211065204; epub ahead of print | PMID: 35287495
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Prediction of the trans-stenotic pressure gradient with arteriography-derived hemodynamic features in patients with idiopathic intracranial hypertension.

Zhang Y, Ma C, Li C, Li X, ... Miao Z, Mo D
The pathogenesis of idiopathic intracranial hypertension (IIH) is attributed to segmental stenosis of the venous sinus. The current treatment paradigm requires a trans-stenotic pressure gradient of ≥8 mmHg or ≥6 mmHg threshold. This study aimed to develop a machine learning screening method to identify patients with IIH using hemodynamic features. A total of 204 venous manometry instances (n = 142, training and validation; n = 62, test) from 135 patients were included. Radiomic features extracted from five arteriography perfusion parameter maps were selected using least absolute shrinkage and selection operator and then entered into support vector machine (SVM) classifiers. The Thr8-23-SVM classifier was created with 23 radiomic features to predict if the pressure gradient was ≥8 mmHg. On an independent test dataset, prediction sensitivity, specificity, accuracy, and AUC were 0.972, 0.846, 0.919, and 0.980, respectively (95% confidence interval: 0.980-1.000). For the 6 mmHg threshold, thr6-28-SVM incorporated 28 features, and its sensitivity, specificity, accuracy, and AUC were 0.923, 0.956, 0.935, and 0.969, respectively (95% confidence interval: 0.927-1.000). The trans-stenotic pressure gradient result was associated with perfusion pattern changes, and SVM classifiers trained with arteriography perfusion map-derived radiomic features could predict the 8 mmHg and 6 mmHg dichotomized trans-stenotic pressure gradients with favorable accuracy.



J Cereb Blood Flow Metab: 07 Mar 2022:271678X221086408; epub ahead of print
Zhang Y, Ma C, Li C, Li X, ... Miao Z, Mo D
J Cereb Blood Flow Metab: 07 Mar 2022:271678X221086408; epub ahead of print | PMID: 35255760
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Systematic review: Association between circulating microRNA expression & stroke.

Fullerton JL, Thomas JM, Gonzalez-Trueba L, Trivett C, ... Quinn TJ, Work LM
This systematic review aimed to establish the range and quality of clinical and preclinical evidence supporting the association of individual microRNAs, and the use of microRNA expression in the diagnosis and prognosis of ischaemic or haemorrhagic stroke. Electronic databases were searched from 1993 to October 2021, using key words relevant to concepts of stroke and microRNA. Studies that met specific inclusion and exclusion criteria were selected for data extraction. To minimise erroneous associations, findings were restricted to microRNAs reported to change in more than two independent studies. Of the papers assessed, 155 papers reported a change in microRNA expression observed in more than two independent studies. In ischaemic studies, two microRNAs were consistently differentially expressed in clinical samples (miR-29b & miR-146a) and four were altered in preclinical samples (miR-137, miR-146a, miR-181b & miR-223-3p). Across clinical and preclinical haemorrhagic studies, four microRNAs were downregulated consistently (miR-26a, miR-126, miR-146a & miR-155). Across included studies, miR-126 and miR-146a were the only two microRNAs to be differentially expressed in clinical and preclinical cohorts following ischaemic or haemorrhagic stroke. Further studies, employing larger populations with consistent methodologies, are required to validate the true clinical value of circulating microRNAs as biomarkers of ischaemic and haemorrhagic stroke.



J Cereb Blood Flow Metab: 02 Mar 2022:271678X221085090; epub ahead of print
Fullerton JL, Thomas JM, Gonzalez-Trueba L, Trivett C, ... Quinn TJ, Work LM
J Cereb Blood Flow Metab: 02 Mar 2022:271678X221085090; epub ahead of print | PMID: 35240874
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Activation of lactate receptor HCAR1 down-modulates neuronal activity in rodent and human brain tissue.

Briquet M, Rocher AB, Alessandri M, Rosenberg N, ... Offermanns S, Chatton JY
Lactate can be used by neurons as an energy substrate to support their activity. Evidence suggests that lactate also acts on a metabotropic receptor called HCAR1, first described in the adipose tissue. Whether HCAR1 also modulates neuronal circuits remains unclear. In this study, using qRT-PCR, we show that HCAR1 is present in the human brain of epileptic patients who underwent resective surgery. In brain slices from these patients, pharmacological HCAR1 activation using a non-metabolized agonist decreased the frequency of both spontaneous neuronal Ca2+ spiking and excitatory post-synaptic currents (sEPSCs). In mouse brains, we found HCAR1 expression in different regions using a fluorescent reporter mouse line and in situ hybridization. In the dentate gyrus, HCAR1 is mainly present in mossy cells, key players in the hippocampal excitatory circuitry and known to be involved in temporal lobe epilepsy. By using whole-cell patch clamp recordings in mouse and rat slices, we found that HCAR1 activation causes a decrease in excitability, sEPSCs, and miniature EPSCs frequency of granule cells, the main output of mossy cells. Overall, we propose that lactate can be considered a neuromodulator decreasing synaptic activity in human and rodent brains, which makes HCAR1 an attractive target for the treatment of epilepsy.



J Cereb Blood Flow Metab: 02 Mar 2022:271678X221080324; epub ahead of print
Briquet M, Rocher AB, Alessandri M, Rosenberg N, ... Offermanns S, Chatton JY
J Cereb Blood Flow Metab: 02 Mar 2022:271678X221080324; epub ahead of print | PMID: 35240875
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Using arterial spin labeling to measure cerebrovascular reactivity in Moyamoya disease: Insights from simultaneous PET/MRI.

Zhao MY, Fan AP, Chen DY, Ishii Y, ... Steinberg GK, Zaharchuk G
Cerebrovascular reactivity (CVR) reflects the CBF change to meet different physiological demands. The reference CVR technique is PET imaging with vasodilators but is inaccessible to most patients. DSC can measure transit time to evaluate patients suspected of stroke, but the use of gadolinium may cause side-effects. Arterial spin labeling (ASL) is a non-invasive MRI technique for CBF measurements. Here, we investigate the effectiveness of ASL with single and multiple post labeling delays (PLD) to replace PET and DSC for CVR and transit time mapping in 26 Moyamoya patients. Images were collected using simultaneous PET/MRI with acetazolamide. CVR, CBF, arterial transit time (ATT), and time-to-maximum (Tmax) were measured in different flow territories. Results showed that CVR was lower in occluded regions than normal regions (by 68 ± 12%, 52 ± 5%, and 56 ± 9%, for PET, single- and multi-PLD PCASL, respectively, all p < 0.05). Multi-PLD PCASL correlated slightly higher with PET (CCC = 0.36 and 0.32 in affected and unaffected territories respectively). Vasodilation caused ATT to reduce by 4.5 ± 3.1% (p < 0.01) in occluded regions. ATT correlated significantly with Tmax (R2 > 0.35, p < 0.01). Therefore, multi-PLD ASL is recommended for CVR studies due to its high agreement with the reference PET technique and the capability of measuring transit time.



J Cereb Blood Flow Metab: 01 Mar 2022:271678X221083471; epub ahead of print
Zhao MY, Fan AP, Chen DY, Ishii Y, ... Steinberg GK, Zaharchuk G
J Cereb Blood Flow Metab: 01 Mar 2022:271678X221083471; epub ahead of print | PMID: 35236136
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Extremely low frequency electromagnetic stimulation reduces ischemic stroke volume by improving cerebral collateral blood flow.

Kemps H, Dessy C, Dumas L, Sonveaux P, ... Lemmens R, Bronckaers A
Extremely low frequency electromagnetic stimulation (ELF-EMS) has been considered as a neuroprotective therapy for ischemic stroke based on its capacity to induce nitric oxide (NO) signaling. Here, we examined whether ELF-EMS reduces ischemic stroke volume by stimulating cerebral collateral perfusion. Moreover, the pathway responsible for ELF-EMS-induced NO production was investigated. ELF-EMS diminished infarct growth following experimental stroke in collateral-rich C57BL/6 mice, but not in collateral-scarce BALB/c mice, suggesting that decreased lesion sizes after ELF-EMS results from improved collateral blood flow. In vitro analysis demonstrated that ELF-EMS increased endothelial NO levels by stimulating the Akt-/eNOS pathway. Furthermore, ELF-EMS augmented perfusion in the hind limb of healthy mice, which was mediated by enhanced Akt-/eNOS signaling. In healthy C57BL/6 mouse brains, ELF-EMS treatment increased cerebral blood flow in a NOS-dependent manner, whereas no improvement in cerebrovascular perfusion was observed in collateral-sparse BALB/c mice. In addition, ELF-EMS enhanced cerebral blood flow in both the contra- and ipsilateral hemispheres of C57BL/6 mice subjected to experimental ischemic stroke. In conclusion, we showed that ELF-EMS enhances (cerebro)vascular perfusion by stimulating NO production, indicating that ELF-EMS could be an attractive therapeutic strategy for acute ischemic stroke by improving cerebral collateral blood flow.



J Cereb Blood Flow Metab: 24 Feb 2022:271678X221084410; epub ahead of print
Kemps H, Dessy C, Dumas L, Sonveaux P, ... Lemmens R, Bronckaers A
J Cereb Blood Flow Metab: 24 Feb 2022:271678X221084410; epub ahead of print | PMID: 35209740
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Neurovascular coupling on trial: How the number of trials completed impacts the accuracy and precision of temporally derived neurovascular coupling estimates.

Burma JS, Van Roessel RK, Oni IK, Dunn JF, Smirl JD
Standard practices for quantifying neurovascular coupling (NVC) with transcranial Doppler ultrasound (TCD) require participants to complete one-to-ten repetitive trials. However, limited empirical evidence exists regarding how the number of trials completed influences the validity and reliability of temporally derived NVC metrics. Secondary analyses was performed on 60 young healthy participants (30 females/30 males) who completed eight cyclical eyes-closed (20-seconds), eyes-open (40-seconds) NVC trials, using the \"Where\'s Waldo?\" visual paradigm. TCD data was obtained in posterior and middle cerebral arteries (PCA and MCA, respectively). The within-day (n = 11) and between-day (n = 17) reliability were assessed at seven- and three-time points, respectively. Repeat testing from the reliability aims were also used for the concurrent validity analysis (n = 160). PCA metrics (i.e., baseline, peak, percent increase, and area-under-the-curve) demonstrated five trials produced excellent intraclass correlation coefficient (ICC) 95% confidence intervals for validity and within-day reliability (>0.900), whereas between-day reliability was good-to-excellent (>0.750). Likewise, 95% confidence intervals for coefficient of variation (CoV) measures ranged from acceptable (<20%) to excellent (<5%) with five-or-more trials. Employing fewer than five trials produced poor/unacceptable ICC and CoV metrics. Future NVC, TCD-based research should therefore have participants complete a minimum of five trials when quantifying the NVC response with TCD via a \"Where\'s Waldo?\" paradigm.



J Cereb Blood Flow Metab: 24 Feb 2022:271678X221084400; epub ahead of print
Burma JS, Van Roessel RK, Oni IK, Dunn JF, Smirl JD
J Cereb Blood Flow Metab: 24 Feb 2022:271678X221084400; epub ahead of print | PMID: 35209741
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Comparison of three novel radiotracers for GluN2B-containing NMDA receptors in non-human primates: -[C]NR2B-Me, -[F]of-Me-NB1, and -[F]of-NB1.

Smart K, Zheng MQ, Ahmed H, Fang H, ... Huang Y, Carson RE
The NMDA receptor GluN2B subunit is a target of interest in neuropsychiatric disorders but to date there is no selective radiotracer available to quantify its availability in vivo. Here we report direct comparisons in non-human primates of three GluN2B-targeting radioligands: (R)-[11C]NR2B-Me, (R)-[18F]OF-Me-NB1, and (S)-[18F]OF-NB1. Plasma free fraction, metabolism, tissue distribution and kinetics, and quantitative kinetic modeling methods and parameters were evaluated in two adult rhesus macaques. Free fraction in plasma was <2% for (R)-[11C]NR2B-Me and (R)-[18F]OF-Me-NB1 and higher for (S)-[18F]OF-NB1 (15%). All radiotracers showed good brain uptake and distribution throughout grey matter, with substantial (>68%) blockade across the brain by the GluN2B-targeting drug Co-101,244 (0.25 mg/kg), including in the cerebellum. Time-activity curves were well-fitted by the one-tissue compartment model, with volume of distribution values of 20-40 mL/cm3 for (R)-[11C]NR2B-Me, 8-16 mL/cm3 for (R)-[18F]OF-Me-NB1, and 15-35 mL/cm3 for (S)-[18F]OF-NB1. Estimates of regional non-displaceable binding potential were in the range of 2-3 for (R)-[11C]NR2B-Me and (S)-[18F]-OF-NB1, and 0.5-1 for (R)-[18F]OF-Me-NB1. Altogether, each radiotracer showed an acceptable profile for quantitative imaging of GluN2B. (S)-[18F]OF-NB1 has particularly promising imaging characteristics for potential translation into humans. However, the source of unexpected displaceable binding in the cerebellum for each of these compounds requires further investigation.



J Cereb Blood Flow Metab: 24 Feb 2022:271678X221084416; epub ahead of print
Smart K, Zheng MQ, Ahmed H, Fang H, ... Huang Y, Carson RE
J Cereb Blood Flow Metab: 24 Feb 2022:271678X221084416; epub ahead of print | PMID: 35209743
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Altered functional connectivity during hypoglycaemia in type 1 diabetes.

Jacob P, Nwokolo M, Cordon SM, Macdonald IA, ... O\'Daly O, Choudhary P
Behavioural responses to hypoglycaemia require coordinated recruitment of broadly distributed networks of interacting brain regions. We investigated hypoglycaemia-related changes in brain connectivity in people without diabetes (ND) and with type 1 diabetes with normal (NAH) or impaired (IAH) hypoglycaemia awareness. Two-step hyperinsulinaemic hypoglycaemic clamps were performed in 14 ND, 15 NAH and 22 IAH participants. BOLD timeseries were acquired at euglycaemia (5.0 mmol/L) and hypoglycaemia (2.6 mmol/L), with symptom and counter-regulatory hormone measurements. We investigated hypoglycaemia-related connectivity changes using established seed regions for the default mode (DMN), salience (SN) and central executive (CEN) networks and regions whose activity is modulated by hypoglycaemia: the thalamus and right inferior frontal gyrus (RIFG). Hypoglycaemia-induced changes in the DMN, SN and CEN were evident in NAH (all p < 0.05), with no changes in ND or IAH. However, in IAH there was a reduction in connectivity between regions within the RIFG (p = 0.001), not evident in the ND or NAH groups. We conclude that hypoglycaemia induces coordinated recruitment of the DMN and SN in diabetes with preserved hypoglycaemia awareness which is absent in IAH and ND. Changes in connectivity in the RIFG, a region associated with attentional modulation, may be key in impaired hypoglycaemia awareness.



J Cereb Blood Flow Metab: 24 Feb 2022:271678X221082911; epub ahead of print
Jacob P, Nwokolo M, Cordon SM, Macdonald IA, ... O'Daly O, Choudhary P
J Cereb Blood Flow Metab: 24 Feb 2022:271678X221082911; epub ahead of print | PMID: 35209745
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Machine learning based analysis of stroke lesions on mouse tissue sections.

Damigos G, Zacharaki EI, Zerva N, Pavlopoulos A, ... Mourouzis I, Lourbopoulos A
An unbiased, automated and reliable method for analysis of brain lesions in tissue after ischemic stroke is missing. Manual infarct volumetry or by threshold-based semi-automated approaches is laborious, and biased to human error or biased by many false -positive and -negative data, respectively. Thereby, we developed a novel machine learning, atlas-based method for fully automated stroke analysis in mouse brain slices stained with 2% Triphenyltetrazolium-chloride (2% TTC), named \"StrokeAnalyst\", which runs on a user-friendly graphical interface. StrokeAnalyst registers subject images on a common spatial domain (a novel mouse TTC- brain atlas of 80 average mathematical images), calculates pixel-based, tissue-intensity statistics (z-scores), applies outlier-detection and machine learning (Random-Forest) models to increase accuracy of lesion detection, and produces volumetry data and detailed neuroanatomical information per lesion. We validated StrokeAnalyst in two separate experimental sets using the filament stroke model. StrokeAnalyst detects stroke lesions in a rater-independent and reproducible way, correctly detects hemispheric volumes even in presence of post-stroke edema and significantly minimizes false-positive errors compared to threshold-based approaches (false-positive rate 1.2-2.3%, p < 0.05). It can process scanner-acquired, and even smartphone-captured or pdf-retrieved images. Overall, StrokeAnalyst surpasses all previous TTC-volumetry approaches and increases quality, reproducibility and reliability of stroke detection in relevant preclinical models.



J Cereb Blood Flow Metab: 24 Feb 2022:271678X221083387; epub ahead of print
Damigos G, Zacharaki EI, Zerva N, Pavlopoulos A, ... Mourouzis I, Lourbopoulos A
J Cereb Blood Flow Metab: 24 Feb 2022:271678X221083387; epub ahead of print | PMID: 35209753
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:

This program is still in alpha version.