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Cerebrovascular abnormalities have emerged as a preclinical manifestation of Alzheimer’s disease and frontotemporal dementia, diseases characterized by the accumulation of hyperphosphorylated forms of the microtubule-associated protein tau. However, it is unclear whether tau contributes to these neurovascular alterations independent of neurodegeneration. We report that mice expressing mutated tau exhibit a selective suppression of neural activity-induced cerebral blood flow increases that precedes tau pathology and cognitive impairment. This dysfunction is attributable to a reduced vasodilatation of intracerebral arterioles and is reversible by reducing tau production. Mechanistically, the failure of neurovascular coupling involves a tau-induced dissociation of neuronal nitric oxide synthase (nNOS) from postsynaptic density 95 (PSD95) and a reduced production of the potent vasodilator nitric oxide during glutamatergic synaptic activity. These data identify glutamatergic signaling dysfunction and nitric oxide deficiency as yet-undescribed early manifestations of tau pathobiology, independent of neurodegeneration, and provide a mechanism for the neurovascular alterations observed in the preclinical stages of tauopathies.Park et al. demonstrate in tauopathy models that tau disrupts the interaction between neuronal nitric oxide synthase and PSD95, uncoupling glutamatergic synaptic activity from nitric oxide production and dampening the hemodynamic response to activation.

The ApoE4 allele is associated with increased risk of small vessel disease, which is a cause of vascular cognitive impairment. Here, we report that mice with targeted replacement (TR) of the ApoE gene with human ApoE4 have reduced neocortical cerebral blood flow compared to ApoE3-TR mice, an effect due to reduced vascular density rather than slowing of microvascular red blood cell flow. Furthermore, homeostatic mechanisms matching local delivery of blood flow to brain activity are impaired in ApoE4-TR mice. In a model of cerebral hypoperfusion, these cerebrovascular alterations exacerbate damage to the white matter of the corpus callosum and worsen cognitive dysfunction. Using 3-photon microscopy we found that the increased white matter damage is linked to an enhanced reduction of microvascular flow resulting in local hypoxia. Such alterations may be responsible for the increased susceptibility to hypoxic-ischemic lesions in the subcortical white matter of individuals carrying the ApoE4 allele. ApoE4 is a risk factor for small vessel disease, which can lead to cognitive impairment. Here the authors assess the microvasculature of the corpus callosum using 3-photon microscopy and find that mice expressing the ApoE4 allele are more susceptible than wild-type to white matter injury and cognitive impairment in a model of hypoperfusion-induced hypoxia.

Background Cerebral amyloid angiopathy (CAA) is a devastating condition common in patients with Alzheimer’s disease but also observed in the general population. Vascular oxidative stress and neurovascular dysfunction have been implicated in CAA but the cellular source of reactive oxygen species (ROS) and related signaling mechanisms remain unclear. We tested the hypothesis that brain border-associated macrophages (BAM), yolk sac-derived myeloid cells closely apposed to parenchymal and leptomeningeal blood vessels, are the source of radicals through the Aβ-binding innate immunity receptor CD36, leading to neurovascular dysfunction, CAA, and cognitive impairment. Methods Tg2576 mice and WT littermates were transplanted with CD36 −/− or CD36 +/+ bone marrow at 12-month of age and tested at 15 months. This approach enables the repopulation of perivascular and leptomeningeal compartments with CD36 −/− BAM. Neurovascular function was tested in anesthetized mice equipped with a cranial window in which cerebral blood flow was monitored by laser-Doppler flowmetry. Amyloid pathology and cognitive function were also examined. Results The increase in blood flow evoked by whisker stimulation (functional hyperemia) or by endothelial and smooth muscle vasoactivity was markedly attenuated in WT → Tg2576 chimeras but was fully restored in CD36 −/−  → Tg2576 chimeras, in which BAM ROS production was suppressed. CAA-associated Aβ 1-40 , but not Aβ 1-42 , was reduced in CD36 −/−  → Tg2576 chimeras. Similarly, CAA, but not parenchymal plaques, was reduced in CD36 −/−  → Tg2576 chimeras. These beneficial vascular effects were associated with cognitive improvement. Finally, CD36 −/− mice were able to more efficiently clear exogenous Aβ 1-40 injected into the neocortex or the striatum. Conclusions CD36 deletion in BAM suppresses ROS production and rescues the neurovascular dysfunction and damage induced by Aβ. CD36 deletion in BAM also reduced brain Aβ 1-40 and ameliorated CAA without affecting parenchyma plaques. Lack of CD36 enhanced the vascular clearance of exogenous Aβ. Restoration of neurovascular function and attenuation of CAA resulted in a near complete rescue of cognitive function. Collectively, these data implicate brain BAM in the pathogenesis of CAA and raise the possibility that targeting BAM CD36 is beneficial in CAA and other conditions associated with vascular Aβ deposition and damage. Graphical Abstract

INTRODUCTION: Brain metastasis from gastric cancer is rare (0.5%) and often occurs with metastasis to other organs. We herein describe a very rare patient with a solitary brain metastasis from residual gastric cancer with no metastasis to other organs.CASE PRESENTATION: The patient was an 82-year-old man who visited a previous institution for anemia. Upper gastrointestinal endoscopy revealed a type 2 tumor extending from the esophagogastric junction to the upper part of the residual gastric body. Biopsy revealed tubular differentiated adenocarcinoma, and he was referred to our institution. He had a history of distal gastrectomy for a gastric ulcer in his 30s. After contrast-enhanced CT, we diagnosed residual gastric cancer (cT4aN + M0 cStage III). After three courses of preoperative chemotherapy with S-1 plus oxaliplatin, the patient underwent open total resection of the residual stomach, lower esophagectomy, D2 dissection, and Roux-en-Y reconstruction and was discharged without postoperative complications. Six months after surgery, thoracic and abdominal contrast-enhanced CT showed no apparent recurrence. However, 1 month later, he began to experience speech difficulties and mobility issues, and head CT revealed a 3-cm tumor in the left frontal lobe. After whole-body contrast-enhanced CT and PET-CT, the brain tumor was confirmed as a solitary lesion with no metastasis to other organs. The patient underwent open brain tumor resection, and pathology diagnosed brain metastasis from residual gastric cancer. Postoperatively, he underwent radiation therapy (40 Gy in 8 fractions) to the tumor cavity. At the time of writing, 24 months have passed since the gastrectomy and 16 months have passed since the removal of the brain tumor, with no significant neurological damage or other evidence of distant metastasis.CONCLUSIONS: We experienced an extremely rare case of a solitary brain metastasis after residual gastric cancer surgery. Our findings suggest that aggressive local treatments for brain metastasis, including surgical resection and radiotherapy, may contribute to improvements in symptoms and prognosis.

Subependymoma is a benign, slow-growing tumor that arises from the ventricular wall. Although often asymptomatic, it can obstruct cerebrospinal fluid flow, leading to hydrocephalus. Most subependymomas are unilateral, typically located in the fourth ventricle, followed by the lateral ventricles. Bilateral involvement of the lateral ventricles is extremely rare. We report the case of a 62-year-old man with bilateral subependymomas located in the anterior horns of both lateral ventricles, who presented with impaired consciousness due to epilepsy. Nineteen years earlier, the tumor in the anterior horn of the left lateral ventricle had been resected via craniotomy with frontal lobe uncapping. The lesion in the right lateral ventricle, initially small, gradually enlarged over two decades and was subsequently resected using flexible neuroendoscopy. This approach allowed safe and effective tumor removal within a spacious intraventricular working environment while maintaining minimal invasiveness. In cases involving relatively small and hypovascular intraventricular tumors, flexible neuroendoscopy represents a viable minimally invasive surgical option. Continued technological advancements are anticipated to further enhance the safety and applicability of neuroendoscopic tumor resections.

Hypercapnia induces potent vasodilation in the cerebral circulation. Although it has long been known that prostanoids participate in the cerebrovascular effects of hypercapnia, the role of prostaglandin E2 (PGE2) and PGE2 receptors have not been fully investigated. In this study, we sought to determine whether cyclooxygenase-1 (COX-1)-derived PGE2 and EP1 receptors are involved in the cerebrovascular response induced by hypercapnia. Cerebral blood flow (CBF) was recorded by laser-Doppler flowmetry in the somatosenasory cortex of anesthetized male EP1-/- mice and wild type (WT) littermates. In WT mice, neocortical application of the EP1 receptor antagonist SC-51089 attenuated the increase in CBF elicited by systemic hypercapnia (pCO2 = 50-60 mmHg). SC-51089 also attenuated the increase in CBF produced by neocortical treatment of arachidonic acid or PGE2. These CBF responses were also attenuated in EP1-/- mice. In WT mice, the COX-1 inhibitor SC-560, but not the COX-2 inhibitor NS-398, attenuated the hypercapnic CBF increase. Neocortical application of exogenous PGE2 restored the attenuation in resting CBF and the hypercapnic response induced by SC-560. In contrast, exogenous PGE2 failed to rescue the attenuation both in WT mice induced by SC-51089 and EP1-/- mice, attesting to the obligatory role of EP1 receptors in the response. These findings indicate that the hypercapnic vasodilatation depends on COX-1-derived PGE2 acting on EP1 receptors and highlight the critical role that COX-1-derived PGE2 and EP1 receptors play in the hypercapnic regulation of the cerebral circulation.

Chordoma is a rare malignant bone tumor arising from notochordal tissue. Conventional treatments, such as radical resection and high-dose irradiation, frequently fail to control the tumor, resulting in recurrence and re-growth. In this study, genetic analysis of the tumor in a 72-year-old male patient with refractory conventional chordoma of the skull base revealed a high tumor mutational burden (TMB) and mutations in the MSH6 and MLH1 genes, which are found in Lynch syndrome. The patient and his family had a dense cancer history, and subsequent germline genetic testing revealed Lynch syndrome. This is the first report of a chordoma that has been genetically proven to be Lynch syndrome. Chordomas usually have low TMB; however, this is an unusual case, because the TMB was high, and immune checkpoint inhibitors effectively controlled the tumor. This case provides a basis for determining the indications for immunotherapy of chordoma based on the genetic analysis. Therefore, further extensive genetic analysis in the future will help to stratify the treatment of chordoma.

Although there have been several investigations regarding acute brain injury after subarachnoid hemorrhage (SAH), the pathological conditions of severe SAH are unclear. In this study, we pursued the characteristics of cerebrovascular injury in the hyperacute phase after experimentally induced severe SAH. Twenty-three male Sprague-Dawley rats were subjected to sham or SAH operation using the endovascular perforation method and were evaluated for brain edema, blood-brain barrier (BBB) permeability, and arterial endothelial cell injury at 5 min after SAH (experiment 1). Next, animals were examined for functional and morphological changes of cerebral artery for 30 min after an acetazolamide injection administered 5 min after SAH (experiment 2). In experiment 1, while cerebral blood flow (CBF) was reduced, brain edema was not observed in SAH-operated rats. BBB permeability detected by immunoglobulin G extravasation was observed in the optic tract and was accompanied by the upregulation of phosphorylated extracellular signal-regulated kinase (ERK)-positive astrocytes. In addition, the number of phosphorylated ERK-positive endothelial cell in the distal middle cerebral artery (MCA) was significantly increased by SAH. In experiment 2, CBF in non-lethal SAH rats was reduced, and no response to acetazolamide was detected. Conversely, CBF in lethal SAH increased due to acetazolamide, although the value of CBF was low. Furthermore, there was significant narrowing of the MCA in SAH-operated rats. The findings suggest that the optic tract and the cerebral artery are the most vulnerable areas regarding cerebrovascular injury in a hyperacute phase after severe SAH and that they are associated with fatal outcomes.

Background It remains to be elucidated whether dipeptidylpeptidase-4 (DPP-4) inhibitor can ameliorate cardiovascular injury in salt-sensitive hypertension. The present study was undertaken to test our hypothesis that linagliptin, a DPP-4 inhibitor, administration initiated after onset of hypertension and cardiac hypertrophy can ameliorate cardiovascular injury in Dahl salt-sensitive hypertensive rats (DS rats). Methods High-salt loaded DS rats with established hypertension and cardiac hypertrophy were divided into two groups, and were orally given (1) vehicle or (2) linagliptin (3 mg/kg/day) once a day for 4 weeks, and cardiovascular protective effects of linagliptin in DS rats were evaluated. Results Linagliptin did not significantly affect blood pressure and blood glucose levels in DS rats. Linagliptin significantly lessened cardiac hypertrophy in DS rats, as estimated by cardiac weight and echocardiographic parameters. Linagliptin significantly ameliorated cardiac fibrosis, cardiac macrophage infiltration, and coronary arterial remodeling in DS rats. Furthermore, linagliptin significantly mitigated the impairment of vascular function in DS rats, as shown by the improvement of acetylcholine-induced or sodium nitroprusside-induced vascular relaxation by linagliptin. These cardiovascular protective effects of linagliptin were associated with the attenuation of oxidative stress, NADPH oxidase subunits, p67 phox and p22 phox , and angiotensin-converting enzyme (ACE). Conclusions Our results provided the experimental evidence that linagliptin treatment initiated after the appearance of hypertension and cardiac hypertrophy protected against cardiovascular injury induced by salt-sensitive hypertension, independently of blood pressure and blood glucose. These beneficial effects of linagliptin seem to be attributed to the reduction of oxidative stress and ACE.