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Normal tension glaucoma (NTG) is labelled when typical glaucomatous disc changes, visual field defects and open anterior chamber angles are associated with intraocular pressure (IOP) constantly below 21 mmHg. Chronic low vascular perfusion, Raynaud's phenomenon, migraine, nocturnal systemic hypotension and over-treated systemic hypertension are the main causes of normal tension glaucoma. Goldmann applanation tonometry, gonioscopy, slit lamp biomicroscopy, optical coherence tomography and visual field analysis are the main tools of investigation for the diagnosis of NTG. Management follows the same principles of treatment for other chronic glaucomas: To reduce IOP by a substantial amount, sufficient to prevent disabling visual loss. Treatment is generally aimed to lower IOP by 30% from pre-existing levels to 12-14 mmHg. Betaxolol, brimonidine, prostaglandin analogues, trabeculectomy (in refractory cases), systemic calcium channel blockers (such as nifedipine) and 24-hour monitoring of blood pressure are considered in the management of NTG. The present review summarises risk factors, causes, pathogenesis, diagnosis and management of NTG.

Non-occlusive mesenteric ischemia is a rare but often fatal condition that occurs due to spasms in the splanchnic arteries leading to hypoperfusion, cellular death, bowel ischemia, and eventually perforation. Having a high clinical suspicion in the correct setting is crucial to identify and treating the medical condition quickly. This is a unique case of an 82-year-old Caucasian male who presented with peritonitis secondary to acute mesenteric ischemia caused by hypotension leading to the eventual finding of bowel ischemia and perforation. J MEDICINE 2024; 25: 176-178

Background Microglial-mediated neuroinflammation plays an important role in vascular dementia, and modulating neuroinflammation has emerged as a promising treatment target. Nicotinamide adenine dinucleotide (NAD + ) shows anti-inflammatory and anti-oxidant effects in many neurodegenerative disease models, but its role in the chronic cerebral hypoperfusion (CCH) is still unclear. Methods The bilateral common carotid artery occlusion (BCCAO) was performed to establish CCH models in Sprague-Dawley rats. The rats were given daily intraperitoneal injection of NAD + for 8 weeks. The behavioral test and markers for neuronal death and neuroinflammation were analyzed. Mitochondrial damage and ROS production in microglia were also assessed. RNA-seq was performed to investigate the mechanistic pathway changes. For in vitro studies, Sirt1 was overexpressed in BV2 microglial cells to compare with NAD + treatment effects on mitochondrial injury and neuroinflammation. Results NAD + administration rescued cognitive deficits and inhibited neuroinflammation by protecting mitochondria and decreasing ROS production in CCH rats. Results of mechanistic pathway analysis indicated that the detrimental effects of CCH might be associated with decreased gene expression of PPAR-γ co-activator1α (PGC-1α) and its upstream transcription factor Sirt1, while NAD + treatment markedly reversed their decrease. In vitro study confirmed that NAD + administration had protective effects on hypoxia-induced neuroinflammation and mitochondrial damage, as well as ROS production in BV2 microglia via Sirt1/PGC-1α pathway. Sirt1 overexpression mimicked the protective effects of NAD + treatment in BV2 microglia. Conclusions NAD + ameliorated cognitive impairment and dampened neuroinflammation in CCH models in vivo and in vitro, and these beneficial effects were associated with mitochondrial protection and ROS inhibition via activating Sirt1/PGC-1α pathway.

Vascular cognitive impairment and dementia (VCID) is commonly caused by vascular injuries in cerebral large and small vessels and is a key driver of age-related cognitive decline. Severe VCID includes post-stroke dementia, subcortical ischemic vascular dementia, multi-infarct dementia, and mixed dementia. While VCID is acknowledged as the second most common form of dementia after Alzheimer’s disease (AD) accounting for 20% of dementia cases, VCID and AD frequently coexist. In VCID, cerebral small vessel disease (cSVD) often affects arterioles, capillaries, and venules, where arteriolosclerosis and cerebral amyloid angiopathy (CAA) are major pathologies. White matter hyperintensities, recent small subcortical infarcts, lacunes of presumed vascular origin, enlarged perivascular space, microbleeds, and brain atrophy are neuroimaging hallmarks of cSVD. The current primary approach to cSVD treatment is to control vascular risk factors such as hypertension, dyslipidemia, diabetes, and smoking. However, causal therapeutic strategies have not been established partly due to the heterogeneous pathogenesis of cSVD. In this review, we summarize the pathophysiology of cSVD and discuss the probable etiological pathways by focusing on hypoperfusion/hypoxia, blood–brain barriers (BBB) dysregulation, brain fluid drainage disturbances, and vascular inflammation to define potential diagnostic and therapeutic targets for cSVD.

Cerebrovascular disease (CVD) and Alzheimer’s disease (AD) have more in common than their association with ageing. They share risk factors and overlap neuropathologically. Most patients with AD have Aβ amyloid angiopathy and degenerative changes affecting capillaries, and many have ischaemic parenchymal abnormalities. Structural vascular disease contributes to the ischaemic abnormalities in some patients with AD. However, the stereotyped progression of hypoperfusion in this disease, affecting first the precuneus and cingulate gyrus, then the frontal and temporal cortex and lastly the occipital cortex, suggests that other factors are more important, particularly in early disease. Whilst demand for oxygen and glucose falls in late disease, functional MRI, near infrared spectroscopy to measure the saturation of haemoglobin by oxygen, and biochemical analysis of myelin proteins with differential susceptibility to reduced oxygenation have all shown that the reduction in blood flow in AD is primarily a problem of inadequate blood supply, not reduced metabolic demand. Increasing evidence points to non-structural vascular dysfunction rather than structural abnormalities of vessel walls as the main cause of cerebral hypoperfusion in AD. Several mediators are probably responsible. One that is emerging as a major contributor is the vasoconstrictor endothelin-1 (EDN1). Whilst there is clearly an additive component to the clinical and pathological effects of hypoperfusion and AD, experimental and clinical observations suggest that the disease processes also interact mechanistically at a cellular level in a manner that exacerbates both. The elucidation of some of the mechanisms responsible for hypoperfusion in AD and for the interactions between CVD and AD has led to the identification of several novel therapeutic approaches that have the potential to ameliorate ischaemic damage and slow the progression of neurodegenerative disease.

Gut microbiota in interaction with intestinal host tissues influences many brain functions and microbial dysbiosis has been linked with brain disorders, such as neuropsychiatric conditions and Alzheimer’s disease (AD). l-tryptophan metabolites and short-chained fatty acids (SCFA) are major messengers in the microbiota-brain axis. Aryl hydrocarbon receptors (AhR) are main targets of tryptophan metabolites in brain microvessels which possess an enriched expression of AhR protein. The Ah receptor is an evolutionarily conserved, ligand-activated transcription factor which is not only a sensor of xenobiotic toxins but also a pleiotropic regulator of both developmental processes and age-related tissue degeneration. Major microbiota-produced tryptophan metabolites involve indole derivatives, e.g., indole 3-pyruvic acid, indole 3-acetaldehyde, and indoxyl sulfate, whereas indoleamine and tryptophan 2,3-dioxygenases (IDO/TDO) of intestine host cells activate the kynurenine (KYN) pathway generating KYN metabolites, many of which are activators of AhR signaling. Chronic kidney disease (CKD) increases the serum level of indoxyl sulfate which promotes AD pathogenesis, e.g., it disrupts integrity of blood–brain barrier (BBB) and impairs cognitive functions. Activation of AhR signaling disturbs vascular homeostasis in brain; (i) it controls blood flow via the renin-angiotensin system, (ii) it inactivates endothelial nitric oxide synthase (eNOS), thus impairing NO production and vasodilatation, and (iii) it induces oxidative stress, stimulates inflammation, promotes cellular senescence, and enhances calcification of vascular walls. All these alterations are evident in cerebral amyloid angiopathy (CAA) in AD pathology. Moreover, AhR signaling can disturb circadian regulation and probably affect glymphatic flow. It seems plausible that dysbiosis of gut microbiota impairs the integrity of BBB via the activation of AhR signaling and thus aggravates AD pathology.Key messagesDysbiosis of gut microbiota is associated with dementia and Alzheimer’s disease.Tryptophan metabolites are major messengers from the gut host-microbiota to brain.Tryptophan metabolites activate aryl hydrocarbon receptor (AhR) signaling in brain.The expression of AhR protein is enriched in brain microvessels and blood-brain barrier.Tryptophan metabolites disturb brain vascular integrity via AhR signaling.Dysbiosis of gut microbiota promotes inflammation and AD pathology via AhR signaling.

A reduction in cerebral blood flow (CBF) has been observed during spaceflight and bed rest. We aimed to examine the magnitude and regional heterogeneity of the decrease in CBF during bed rest compared to posture changes on Earth. Seventeen participants (age, 29 ± 9 years, 7 females) were studied in the upright and supine posture and over 3 days of bed rest. We assessed blood flow via duplex ultrasonography in the internal carotid (ICA) and vertebral arteries (VA), and via transcranial Doppler of the middle cerebral artery (MCAv). Mean arterial pressure (MAP) and end‐tidal CO 2 () were assessed at all time points. By day 3, total CBF (1078 ± 302 to 853 ± 245 mL min −1 , P <  0.0001) and MCAv (61 ± 15 to 49 ± 12 mL min −1 , P <  0.0001) were decreased compared to the supine posture. CBF values did not fall below the upright posture (all P  > 0.05) but were lower than a calculated 24‐h mean baseline ( P  = 0.0132). MAP remained stable ( P =  0.971), as did ( P  = 0.0803), while VA blood flow decreased after 24 h and again after 72 h ( P  = 0.0024). These findings indicate that CBF decreases during short‐term bed rest, but not below values observed in the upright posture. What is the central question of this study? Does cerebral blood flow change with bed rest and if yes, are there any regional heterogeneities and what are the underlying mechanisms? What is the main finding and its importance? Cerebral blood flow decreases over bed rest involving both the internal carotid and vertebral artery blood flow. While it does not fall below values in the seated position, it is lower than a 24‐h mean calculated from both seated and supine baseline values. End‐tidal CO 2 and mean arterial pressure are not likely to be mechanisms for the decrease, as they did not change accordingly.

Vascular dementia (VD) is defined as a progressive neurodegenerative disease of cognitive decline, attributable to cerebrovascular factors. Numerous studies have demonstrated that chronic cerebral hypoperfusion (CCH) is associated with the initiation and progression of VD and Alzheimer’s disease (AD). Suitable animal models were established to replicate such pathological condition in experimental research, which contributes largely to comprehending causal relationships between CCH and cognitive impairment. The most widely used experimental model of VD and CCH is permanent bilateral common carotid artery occlusion in rats. In CCH models, changes of learning and memory, cerebral blood flow (CBF), energy metabolism, and neuropathology initiated by ischemia were revealed. However, in order to achieve potential therapeutic targets, particular mechanisms in cognitive and neuropathological changes from CCH to dementia should be investigated. Recent studies have shown that hypoperfusion resulted in a chain of disruption of homeostatic interactions, including oxidative stress, neuroinflammation, neurotransmitter system dysfunction, mitochondrial dysfunction, disturbance of lipid metabolism, and alterations of growth factors. Evidence from experimental studies that elucidate the damaging effects of such imbalances suggests their critical roles in the pathogenesis of VD. The present review provides a summary of the achievements in mechanisms made with the CCH models, permits an understanding of the causative role played by CCH in VD, and highlights preventative and therapeutic prospects.

Vascular cognitive impairment (VCI) describes a wide spectrum of cognitive deficits related to cerebrovascular diseases. Although the loss of blood flow to cortical regions critically involved in cognitive processes must feature as the main driver of VCI, the underlying mechanisms and interactions with related disease processes remain to be fully elucidated. Recent clinical studies of cerebral blood flow measurements have supported the role of chronic cerebral hypoperfusion (CCH) as a major driver of the vascular pathology and clinical manifestations of VCI. Here we review the pathophysiological mechanisms as well as neuropathological changes of CCH. Potential interventional strategies for VCI are also reviewed. A deeper understanding of how CCH can lead to accumulation of VCI-associated pathology could potentially pave the way for early detection and development of disease-modifying therapies, thus allowing preventive interventions instead of symptomatic treatments.

Microglial activation participates in white matter injury after cerebral hypoperfusion. However, the underlying mechanism is unclear. Here, we explore whether activated microglia aggravate white matter injury via complement C3-C3aR pathway after chronic cerebral hypoperfusion. : Adult male Sprague-Dawley rats (n = 80) underwent bilateral common carotid artery occlusion for 7, 14, and 28 days. Cerebral vessel density and blood flow were examined by synchrotron radiation angiography and three-dimensional arterial spin labeling. Neurobehavioral assessments, CLARITY imaging, and immunohistochemistry were performed to evaluate activation of microglia and C3-C3aR pathway. Furthermore, C3aR knockout mice were used to establish the causal relationship of C3-C3aR signaling on microglia activation and white matter injury after hypoperfusion. : Cerebral vessel density and blood flow were reduced after hypoperfusion ( 0.05). Spatial learning and memory deficits and white matter injury were shown ( 0.05). These impairments were correlated with aberrant microglia activation and an increase in the number of reactive microglia adhering to and phagocytosed myelin in the hypoperfusion group ( 0.05), which were accompanied by the up-regulation of complement C3 and its receptors C3aR ( 0.05). Genetic deletion of significantly inhibited aberrant microglial activation and reversed white matter injury after hypoperfusion ( 0.05). Furthermore, the C3aR antagonist SB290157 decreased the number of microglia adhering to myelin ( 0.05), attenuated white matter injury and cognitive deficits in chronic hypoperfusion rats ( 0.05). : Our results demonstrated that aberrant activated microglia aggravate white matter injury via C3-C3aR pathway during chronic hypoperfusion. These findings indicate C3aR plays a critical role in mediating neuroinflammation and white matter injury through aberrant microglia activation, which provides a novel therapeutic target for the small vessel disease and vascular dementia.