Loss of body weight in old 5xFAD mice and the alteration of gut microbiota composition.

The cause of age-related body weight loss in Alzheimer's disease (AD) is unclear. We compared the differences in food intake, malabsorption, locomotor activity, and gut microbiota composition between 5xFAD mice, a useful model of AD, and wild-type (WT) mice to investigate the mechanisms underlying lower body weight in 5xFAD mice. Fifteen-month-old male 5xFAD mice and age-matched WT mice were divided into four groups: a control diet (CD) or a high-fat diet (HFD). After feeding CD or HFD for eight to nine weeks, 5xFAD mice had a significantly lower body weight than WT mice regardless of diet (p < 0.05). Additionally, the 5xFAD mice did not show a reduction in food intake compared to the WT mice regardless of diet. To evaluate malabsorption, we performed a fecal fat test. There was no obvious fecal fat in both the 5xFAD mice and WT mice. However, 5xFAD mice showed greater locomotor activity than WT mice in the Y-maze test. The comprehensive analysis of gut microbiota composition showed that 15-month-old 5xFAD mice had more Proteobacteria population and fewer Actinobacteria and Bifidobacteriales populations than WT mice. To investigate the effects of fructooligosaccharides (FOS), we administrated FOS to 15-month-old 5xFAD mice. FOS administration decreased Proteobacteria and increased Actinobacteria population, although that did not change Bifidobacteriales population. Moreover, cognitive impairment and body weight of 5xFAD mice were not changed by FOS administration. In conclusion, loss of body weight in 15-month-old 5xFAD mice might be partially derived from excess energy output by hyperactivity. Moreover, 15-month-old 5xFAD mice might have unique alteration of gut microbiota composition and the potential resistance to FOS.

The endogenous and exogenous brain-derived neurotrophic factor plays pivotal roles in the pathogenesis of stroke onset in high salt-loaded hypertensive rats.

Brain-derived neurotrophic factor (BDNF) is known to have neuroprotective effects on multiple neurovascular diseases especially poststroke recovery. On the other hand, BDNF reported to increase blood pressure (BP) which is one of the major risk factors for stroke onset. To clarify the conflicting effects on stroke onset, we examined the expression of endogenous BDNF in relation to stroke onset. In addition, we explored the effect of exogenous central BDNF against stroke onset and all-cause mortality as the primary endpoint and BP as the secondary object in hypertensive rats with high-salt diet. In experiment 1, male spontaneously hypertensive stroke-prone rats (SHRSP) were fed a 0.3% (n = 8) or an 8% (n = 22) sodium diet (Na) through 28 days. The SHRSP with 8% Na showed significant increase of stroke onset, all-cause mortality, upregulation of reactive astrocytes, and disruption of blood-brain barrier. BDNF in the rats with 8% Na was significantly upregulated and mainly expressed in reactive astrocytes, whereas phosphorylated tropomyosin-related kinase B did not change by the rich BDNF. In experiment 2, male SHRSP were treated with continuous intracerebroventricular injection of 2.1 µg/day BDNF (n = 10) or the vehicle (Phosphate buffer saline; n = 10) and fed an 8% Na through 24 days. Exogenous central BDNF induced significant increase of BP and heart rate, and exhibited higher stroke onset and all-cause mortality compared with vehicle group. The present study demonstrated that endogenous BDNF were significantly produced in reactive astrocytes in relation to stroke onset regardless of neuroprotection. In addition, exogenous central BDNF increased BP which might be associated with sympathetic nerve activity and provided unfavorable effects on the prognosis of hypertensive rats. As BDNF is still potentially a good candidate for the treatment of neurovascular diseases, we suggest that hypertensive patients need care for the elevation of BP in the clinical trials of BDNF.

Hemodynamic study about cortical hyperintensity belt sign after direct bypass surgery for moyamoya disease.

Transient neurological events (TNEs) are observed after direct bypass surgery in patients with moyamoya disease (MMD). Although a correlation between cortical hyperintensity belt signs (CHBs) and TNEs has been reported, the pathophysiology of CHBs is still unknown. The purpose of this study was to reveal the pathophysiology of CHBs by using dynamic susceptibility contrast-magnetic resonance imaging. Thirty patients with MMD were included in this study. We provided scores (0-2) for the existence of CHBs on postoperative FLAIR images. We placed the ROI for the presented area of CHBs in the images of cerebral blood flow, CBV, and MTT. We calculated the change of the hemodynamic parameters (increase ratio, IR) and analyzed the relationship between IRs, CHB scores, and TNEs. TNEs were observed in 15 cases (50%) and CHBs were detected in 28 cases (93%). TNEs showed significantly higher CHB scores than those without (p < 0.05). The group of CHB score 2 showed a significantly higher CBV IR than the group with of score 0 (p < 0.05). Patients with TNEs showed a significantly higher CBV IR than those without (p < 0.05). As for the cut-off level to predict an appearance of TNEs, the CBV IR was 1.36 by the Receiver Operating Characteristic analysis, and the sensitivity and specificity were 80% respectively. We hypothesize that the pathophysiology of the CHBs are vasogenic edemas because the postoperative CBV increase correlated with the CHBs.

Enhanced oxidative stress contributes to worse prognosis and delayed neurofunctional recovery after striatal intracerebral hemorrhage in 5XFAD mice.

Although Alzheimer's disease (AD) is associated with an increased risk of intracerebral hemorrhage (ICH) caused by hypertension and cerebral amyloid angiopathy, the precise clinical course after hypertensive ICH in AD patients is still unknown. In this study, we investigated how striatal ICH, a frequent site for hypertensive ICH, affected the prognosis of AD. We employed 17- and 18-month-old male 5XFAD (5X) mice and littermate (LT) controls, and striatal ICH was induced by collagenase injection. First, to address the acute effects of ICH on 5X mice, hemorrhagic volume and brain edema were evaluated 3 days after ICH. Next, to address the long-term effects of ICH on 5X mice, morbidity, mortality, neurological function (beam-walking and rotarod tests), and cognitive function (Y-maze and nest-building tests) were monitored. Twenty-eight days later, the animals were euthanized, their brains were isolated, and the cytotoxic alterations were investigated. The results revealed that the acute effects of ICH were not significantly different between 5X and LT mice. In contrast, 5X mice showed significantly higher morbidity and mortality in response to ICH, as well as delayed neurological function recovery, compared to LT mice through 28 days. ICH did not affect cognitive function in either group. Infiltrated macrophages in the perihemorrhagic cortex, gp91phox , p67phox , and COX-2 were significantly increased in 5X mice in response to ICH. We demonstrated that striatal ICH deteriorated prognosis and delayed neurofunctional recovery in 5X mice, which might be associated with enhanced oxidative stress in the presence of AD-like pathology.

The Stabilization of Central Sympathetic Nerve Activation by Renal Denervation Prevents Cerebral Vasospasm after Subarachnoid Hemorrhage in Rats.

The poor prognosis of subarachnoid hemorrhage (SAH) might be associated with sympathetic nerve activation (catecholamine surge) initiated by hypothalamic injury. As renal denervation (RD) has been shown to exert protective effects on cardiovascular dysfunction by suppressing increased central sympathetic nerve activation, we examined whether RD improved the experimental SAH prognosis in this study. Two hundred thirty-eight male Sprague-Dawley rats were divided into sham-operated and SAH-operated groups, and then each rat was further separated into Sham-operated and RD-operated groups. Bilateral RD was performed approximately 45 min after SAH induction. We examined the effect of RD on early brain injury (EBI) and delayed cerebral ischemia (DCI) as a primary endpoint, and also explored the effect on cerebral vasospasm (CVS) as a secondary endpoint. Although RD did not exert significant effects on primary endpoint, RD significantly prevented CVS and reduced SAH-induced increases in the number of phosphorylated extracellular signal-regulated kinase (ERK)-positive endothelial cells, cyclooxygenase-2 expression, and macrophage infiltration in major cerebral arteries. Moreover, RD significantly decreased the areas displaying dopamine ß-hydroxylase and glial fibrillary acidic protein immunopositivity in the paraventricular nucleus of the hypothalamus and serum angiotensin II levels, all of which were increased by SAH. Although RD decreased systolic blood pressure, significant changes in cerebral blood flow were not observed compared with SAH + Sham group. Based on the findings, RD improved CVS by reducing endothelial cell damage and the effects were associated with the stabilization of central sympathetic nerve activation in a SAH model.

Chronic Angiotensin 1-7 Infusion Prevents Angiotensin-II-Induced Cognitive Dysfunction and Skeletal Muscle Injury in a Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is increasingly viewed as a neurological disease accompanied by a systemic disorder. Accumulating evidence supports that angiotensin II and angiotensin 1-7 exert opposite effects on various organs including the brain. However, the interaction between angiotensin II and angiotensin 1-7 in AD remains to be defined. The present study was undertaken to examine the interaction between these peptides in AD. 5XFAD mice, a useful model of AD, were separated into three groups: 1) saline-infused, 2) angiotensin II-infused, and 3) angiotensin II-infused and angiotensin 1-7-co-infused. These peptides were systemically given to 5XFAD mice via osmotic minipump for 4 weeks. Systemic angiotensin II infusion for 4 weeks induced significant hypertension in both wild-type and 5XFAD mice. Angiotensin II induced cognitive abnormality in 5XFAD mice as estimated by the Morris water maze test and the nest building test, and this effect was associated with cerebral blood flow reduction, cortical arterial amyloid-ß deposition, hippocampal inflammation, and neuron loss in 5XFAD mice. In addition, angiotensin II infusion led to gastrocnemius muscle atrophy in 5XFAD mice. Co-infusion of angiotensin 1-7 prevented the above mentioned detrimental effects of angiotensin II in the brain and gastrocnemius muscle in 5XFAD mice, without significant influence on blood pressure. The left ventricular hypertrophic response to angiotensin II was attenuated in 5XFAD mice compared with wild-type mice, which was not significantly altered by co-administration of angiotensin 1-7. Our results show that angiotensin 1-7 counteracts angiotensin II-induced cognitive impairment, brain injury, and skeletal muscle injury in AD mice.

Cortical Venous Reddening Predicts Remote Cerebral Infarction Post Superficial Temporal Artery-Middle Cerebral Artery Bypass in Atherosclerotic Occlusive Cerebrovascular Disease.

BACKGROUND: The superficial temporal artery (STA)-middle cerebral artery (MCA) anastomosis (STA-MCA bypass) currently is performed to prevent atherosclerotic occlusive cerebrovascular disease. However, the benefits of the bypass surgery remain controversial. To ensure consistent surgical benefits, understanding the mechanisms of perioperative cerebral infarction (CI) is required. Moreover, appropriate patient selection procedures must be determined to decrease the rate of perioperative stroke. We retrospectively investigated patients who underwent bypass surgery at our institution and determined that the patients who presented with cortical venous reddening after anastomosis during the surgery developed perioperative CI. METHODS: A total of 45 consecutive patients who underwent bypass surgery were retrospectively investigated. Twenty-five of the 45 patients underwent bypass for atherosclerotic occlusion or stenosis of the internal carotid artery or middle cerebral artery. Preoperative iodine-123-N-isopropyl-iodoamphetamine single-photon emission computed tomography was performed with and without acetazolamide administration. Change in color of the cortical veins was observed on recorded surgical videos, and its correlation with perioperative CI was investigated. RESULTS: We experienced 2 cases of perioperative extensive CI at a region remote from the site of anastomosis. In both cases, retrospective investigation of surgical videos demonstrated reddening of cortical veins soon after the anastomosis procedure. Of all 45 patients, postoperative CI and venous reddening were observed in only these 2 cases. CONCLUSIONS: We determined that patients presenting with cortical venous reddening after anastomosis developed perioperative CI. Cortical venous reddening may be an important predictor for the occurrence of CI after STA-MCA bypass surgery for patients with atherosclerotic occlusive cerebrovascular disease.

Continuous intracerebroventricular injection of Porphyromonas gingivalis lipopolysaccharide induces systemic organ dysfunction in a mouse model of Alzheimer's disease.

Systemic organ dysfunction is one of the important issues for the patients with Alzheimer's disease (AD) and their caregivers. Recent evidences suggest that periodontitis is a possible risk factor for progression of AD and lipopolysaccharide derived from Porphyromonas gingivalis (Pg-LPS) which is a major periodontopathic bacteria induces cognitive impairment in mice. However, the precise relationships between the brain exposure of Pg-LPS and systemic organ dysfunction in AD patients are still undetermined. In this study, we investigated whether brain exposure of Pg-LPS induced systemic organ dysfunction in a model of AD mouse. We employed 6 (young) and 13 (middle-aged) months-old 5XFAD mice and 6 months-old littermate (LT) mice, and treated with intracerebroventricular (ICV) injection of 2 µg Pg-LPS or saline (vehicle). The animals were monitored cognitive functions (Y maze, nest building, and Morris water maze tests), motor functions (wire hang and rotarod tests), physical condition (symptom score), and blood pressure (BP). Twenty-eight days later, their organs were weighted and the organ damages were examined. Continuous ICV injection of 2 µg/day Pg-LPS increased ionized calcium binding adapter molecule-1 (Iba-1) and cluster of differentiation 3 (CD3) positive cells in periventricular area of 5XFAD mice without enhancement of cognitive impairment, amyloid ß protein deposition, expressions of phosphorylated nuclear factor-kappa B (NF-κB) and cyclooxygenase-2 (COX-2). In addition, the Pg-LPS lowered the latency of rotarod test in young 5XAD mice and also reduced symptom score and weight of gastrocnemius muscle in the middle-aged animals. Moreover, the Pg-LPS induced cardiac atrophy in both young and middle-aged 5XFAD mice, and increased Iba-1 positive cells in left ventricle of the young animals. On the other hand, single ICV injection of 2 µg Pg-LPS in 5XFAD and continuous injection of 2 µg/day Pg-LPS in LT mice did not show any positive findings. Our present results demonstrated that continuous brain exposure of Pg-LPS started sarcopenia and cardiac injury without enhancing cognitive impairment in AD model mice.

Spontaneous Repeated Disappearance and Recurrence of Multiple Spinal Intradural Arachnoid Cysts in a Child.

BACKGROUND: Spinal intradural arachnoid cysts are rare in the pediatric population. We present a rare case of intradural spinal arachnoid cysts that spontaneously and repeatedly disappeared and reoccurred. CASE DESCRIPTION: A 2-year-and-8-months-old boy presenting with lower extremity weakness was found to have spinal intradural arachnoid cysts in cervical and thoracolumbar regions at separate times. Although spontaneous disappearance of both lesions was observed, surgical treatment was finally performed for the symptomatic recurrent thoracolumbar lesion. CONCLUSIONS: To the best of our knowledge, this is the first report of spontaneously disappearing and recurring spinal arachnoid cysts.

DPP-4 inhibition with linagliptin ameliorates the progression of premature aging in klotho-/- mice.

BACKGROUND: The potential of anti-aging effect of DPP-4 inhibitors is unknown. This study was performed to determine whether linagliptin, a DPP-4 inhibitor, could protect against premature aging in klotho-/- mice. METHODS: Klotho-/- mice exhibit multiple phenotypes resembling human premature aging, including extremely shortened life span, cognitive impairment, hippocampal neurodegeneration, hair loss, muscle atrophy, hypoglycemia, etc. To investigate the effect of linagliptin on these aging-related phenotypes, male klotho-/- mice were divided into two groups: (1) control group fed the standard diet, and (2) linagliptin group fed the standard diet containing linagliptin. Treatment with linagliptin was performed for 4 weeks. The effect of linagliptin on the above mentioned aging-related phenotypes was examined. RESULTS: Body weight of klotho-/- mice was greater in linagliptin group than in control group (11.1 ± 0.3 vs 9.9 ± 0.3 g; P < 0.01), which was associated with greater gastrocnemius muscle weight (P < 0.01) and greater kidney weight (P < 0.05) in linagliptin group. Thus, linagliptin significantly prevented body weight loss in klotho-/- mice. Survival rate of klotho-/- mice was greater in linagliptin group (93%) compared to control group (67%), although the difference did not reach statistical significance (P = 0.08). None of linagliptin-treated klotho-/- mice had alopecia during the treatment (P < 0.05 vs control klotho-/- mice). Latency of klotho-/- mice in passive avoidance test was larger in linagliptin group than in control group (P < 0.05), indicating the amelioration of cognitive impairment by linagliptin. Cerebral blood flow of klotho-/- mice was larger in linagliptin group than in control group (P < 0.01), being associated with greater cerebral phospho-eNOS levels (P < 0.05) in linagliptin group. Neuronal cell number in hippocampal CA1 region was greater in linagliptin group than in control group (P < 0.05). Linagliptin group had greater cerebral phospho-Akt (P < 0.05) and phospho-CREB (P < 0.05) than control group. Thus, linagliptin ameliorated brain aging in klotho-/- mice. The degree of hypoglycemia in klotho-/- mice was less in linagliptin group than in control group, as estimated by the findings of OGTT. CONCLUSIONS: Out work provided the evidence that DPP-4 inhibition with linagliptin slowed the progression of premature aging in klotho-/- mice, and provided a novel insight into the potential role of DPP-4 in the mechanism of premature aging.

Amyotrophic lateral sclerosis in a patient with Kartagener syndrome.

We present a case of a patient with clinically definite ALS, who had earlier suffered from Kartagener syndrome, which is characterized by the triad comprising chronic sinusitis, bronchiectasis, and situs inversus. Recent linkage and mutational analyses identified several genes that are responsible for Kartagener syndrome. Most of them encode subunits of axonemal dyneins, highlighting the importance of dynein motors to ciliary motility. Recent data indicate that defects in cytoplasmic dynein-mediated retrograde axonal transport are involved in the etiology of ALS. Genes encoding the dynein heavy chain of cytoplasmic and outer arm axonemal dyneins are reported to have similar sequences in their central and 3'-end regions. Although a causal link between ALS and Kartagener syndrome has not yet been definitely established, the precise relationship between disrupted axonemal dynein function in Kartagener syndrome and motor neuron death should be investigated.