Chronic cerebral hypoperfusion: An undefined, relevant entity

Ciacciarelli, Antonio; Sette, Giuliano; Giubilei, Franco; Orzi, Francesco

doi:10.1016/j.jocn.2020.01.026

Cited by 46 publications

(27 citation statements)

References 68 publications

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“…This model is helpful in investigating the mechanisms and effects of long-term chronic cerebral hypoperfusion (Farkas et al, 2007). bCCAo in the rat causes chronic cerebral hypoperfusion mainly in the forebrain and leads to early disruption of the BBB, to white matter rarefaction with axonal and myelin damage, to neuroinflammation, and to hippocampal and cortical neuronal damage (Ciacciarelli et al, 2020). Indeed, the infarcts generated by bCCAo are seen not only in the striatum and the dorsolateral cortex but also in areas such as the hippocampus, thalamus, and hypothalamus (Ciacciarelli et al, 2020).…”

Section: Neuron-astrocyte-microglia Interactions In the Hippocampus Imentioning

confidence: 99%

“…bCCAo in the rat causes chronic cerebral hypoperfusion mainly in the forebrain and leads to early disruption of the BBB, to white matter rarefaction with axonal and myelin damage, to neuroinflammation, and to hippocampal and cortical neuronal damage (Ciacciarelli et al, 2020). Indeed, the infarcts generated by bCCAo are seen not only in the striatum and the dorsolateral cortex but also in areas such as the hippocampus, thalamus, and hypothalamus (Ciacciarelli et al, 2020). Among the plausible explanations for the unexpected brain damages to the latter brain areas are (i) anomalies of the circle of Willis (Kitagawa et al, 1998), (ii) production of neurotoxic molecules that propagate to the hippocampus and cause ischemic damage (Xie et al, 2011), and (iii) overexcitation of the hippocampal neuronal network by glutamate produced after the occlusion.…”

Section: Neuron-astrocyte-microglia Interactions In the Hippocampus Imentioning

confidence: 99%

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An Overview on the Differential Interplay Among Neurons–Astrocytes–Microglia in CA1 and CA3 Hippocampus in Hypoxia/Ischemia

Lana

Ugolini

Giovannini

2020

Front. Cell. Neurosci.

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Neurons have been long regarded as the basic functional cells of the brain, whereas astrocytes and microglia have been regarded only as elements of support. However, proper intercommunication among neurons–astrocytes–microglia is of fundamental importance for the functional organization of the brain. Perturbation in the regulation of brain energy metabolism not only in neurons but also in astrocytes and microglia may be one of the pathophysiological mechanisms of neurodegeneration, especially in hypoxia/ischemia. Glial activation has long been considered detrimental for survival of neurons, but recently it appears that glial responses to an insult are not equal but vary in different brain areas. In this review, we first take into consideration the modifications of the vascular unit of the glymphatic system and glial metabolism in hypoxic conditions. Using the method of triple-labeling fluorescent immunohistochemistry coupled with confocal microscopy (TIC), we recently studied the interplay among neurons, astrocytes, and microglia in chronic brain hypoperfusion. We evaluated the quantitative and morpho-functional alterations of the neuron–astrocyte–microglia triads comparing the hippocampal CA1 area, more vulnerable to ischemia, to the CA3 area, less vulnerable. In these contiguous and interconnected areas, in the same experimental hypoxic conditions, astrocytes and microglia show differential, finely regulated, region-specific reactivities. In both areas, astrocytes and microglia form triad clusters with apoptotic, degenerating neurons. In the neuron–astrocyte–microglia triads, the cell body of a damaged neuron is infiltrated and bisected by branches of astrocyte that create a microscar around it while a microglial cell phagocytoses the damaged neuron. These coordinated actions are consistent with the scavenging and protective activities of microglia. In hypoxia, the neuron–astrocyte–microglia triads are more numerous in CA3 than in CA1, further indicating their protective effects. These data, taken from contiguous and interconnected hippocampal areas, demonstrate that glial response to the same hypoxic insult is not equal but varies significantly. Understanding the differences of glial reactivity is of great interest to explain the differential susceptibility of hippocampal areas to hypoxia/ischemia. Further studies may evidence the differential reactivity of glia in different brain areas, explaining the higher or lower sensitivity of these areas to different insults and whether glia may represent a target for future therapeutic interventions.

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Section: Neuron-astrocyte-microglia Interactions In the Hippocampus Imentioning

confidence: 99%

Section: Neuron-astrocyte-microglia Interactions In the Hippocampus Imentioning

confidence: 99%

An Overview on the Differential Interplay Among Neurons–Astrocytes–Microglia in CA1 and CA3 Hippocampus in Hypoxia/Ischemia

Lana

Ugolini

Giovannini

2020

Front. Cell. Neurosci.

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“…The immobility of the fluid drainage can support PVS's role in different diseases: the possible explanation of the PVS involvement in SVD, is the argued relationship demonstrated between an altered cerebrovascular reactivity (CVR), which is the change in cerebral blood flow in response to a vaso-active stimulus in the so-called neurovascular coupling, the found BBB dysfunction, and the correspondent perivascular inflammation [86]. Therefore, a lacuna should not indicate an enlarged perivascular space, as it is, still nowdays; it should never be the correspondent of the CSF-filled cavities on brain MRI or residual lesion of a small hemorrhage [82,[87][88][89][90][91][92]. Nowadays, it should be more appropriate for the definition "lacuna of presumed vascular origin" to replace the term "lacuna" [20,[93][94][95][96].…”

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confidence: 99%

Small Vessel Disease-Related Dementia: An Invalid Neurovascular Coupling?

Moretti

Caruso

2020

IJMS

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The arteriosclerosis-dependent alteration of brain perfusion is one of the major determinants in small vessel disease, since small vessels have a pivotal role in the brain’s autoregulation. Nevertheless, as far as we know, endothelium distress can potentiate the flow dysregulation and lead to subcortical vascular dementia that is related to small vessel disease (SVD), also being defined as subcortical vascular dementia (sVAD), as well as microglia activation, chronic hypoxia and hypoperfusion, vessel-tone dysregulation, altered astrocytes, and pericytes functioning blood-brain barrier disruption. The molecular basis of this pathology remains controversial. The apparent consequence (or a first event, too) is the macroscopic alteration of the neurovascular coupling. Here, we examined the possible mechanisms that lead a healthy aging process towards subcortical dementia. We remarked that SVD and white matter abnormalities related to age could be accelerated and potentiated by different vascular risk factors. Vascular function changes can be heavily influenced by genetic and epigenetic factors, which are, to the best of our knowledge, mostly unknown. Metabolic demands, active neurovascular coupling, correct glymphatic process, and adequate oxidative and inflammatory responses could be bulwarks in defense of the correct aging process; their impairments lead to a potentially catastrophic and non-reversible condition.

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“…49 Imaging protocols capable of providing a direct assessment of hypoxic stress have the potential to improve the process of patient selection in the sub-acute phase of AIS, as well as in chronic atherosclerotic patients without a complete circle of Willis and with suspected neurological hypoperfusion symptoms such as cognitive deficits. 50 A key question in this context is thus to what extent [ 18 F]FMISO is specific for the ischemic penumbra. An absolute validation using gold standard 15-O PET was beyond the scope of this study.…”

Section: Discussionmentioning

confidence: 99%

The cellular basis of increased PET hypoxia tracer uptake in focal cerebral ischemia with comparison between [¹⁸F]FMISO and [⁶⁴Cu]CuATSM

Little

Arnberg

Jussing

et al. 2020

J Cereb Blood Flow Metab

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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.

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Chronic cerebral hypoperfusion: An undefined, relevant entity

Cited by 46 publications

References 68 publications

An Overview on the Differential Interplay Among Neurons–Astrocytes–Microglia in CA1 and CA3 Hippocampus in Hypoxia/Ischemia

An Overview on the Differential Interplay Among Neurons–Astrocytes–Microglia in CA1 and CA3 Hippocampus in Hypoxia/Ischemia

Small Vessel Disease-Related Dementia: An Invalid Neurovascular Coupling?

The cellular basis of increased PET hypoxia tracer uptake in focal cerebral ischemia with comparison between [¹⁸F]FMISO and [⁶⁴Cu]CuATSM

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Chronic cerebral hypoperfusion: An undefined, relevant entity

Cited by 46 publications

References 68 publications

An Overview on the Differential Interplay Among Neurons–Astrocytes–Microglia in CA1 and CA3 Hippocampus in Hypoxia/Ischemia

An Overview on the Differential Interplay Among Neurons–Astrocytes–Microglia in CA1 and CA3 Hippocampus in Hypoxia/Ischemia

Small Vessel Disease-Related Dementia: An Invalid Neurovascular Coupling?

The cellular basis of increased PET hypoxia tracer uptake in focal cerebral ischemia with comparison between [18F]FMISO and [64Cu]CuATSM

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The cellular basis of increased PET hypoxia tracer uptake in focal cerebral ischemia with comparison between [¹⁸F]FMISO and [⁶⁴Cu]CuATSM