Aggregates of RNA Binding Proteins and ER Chaperones Linked to Exosomes in Granulovacuolar Degeneration of the Alzheimer's Disease Brain.

Granulovacuolar degeneration (GVD) occurs in Alzheimer's disease (AD) brain due to compromised autophagy. Endoplasmic reticulum (ER) function and RNA binding protein (RBP) homeostasis regulate autophagy. We observed that the ER chaperones Glucose - regulated protein, 78 KDa (GRP78/BiP), Sigma receptor 1 (SigR1), and Vesicle-associated membrane protein associated protein B (VAPB) were elevated in many AD patients' subicular neurons. However, those neurons which were affected by GVD showed lower chaperone levels, and there was only minor co-localization of chaperones with GVD bodies (GVBs), suggesting that neurons lacking sufficient chaperone-mediated proteostasis enter the GVD pathway. Consistent with this notion, granular, incipient pTau aggregates in human AD and pR5 tau transgenic mouse neurons were regularly co-localized with increased chaperone immunoreactivity, whereas neurons with mature neurofibrillary tangles lacked both the chaperone buildup and significant GVD. On the other hand, APP/PS1 (APPswe/PSEN1dE9) transgenic mouse hippocampal neurons that are devoid of pTau accumulation displayed only few GVBs-like vesicles, which were still accompanied by prominent chaperone buildup. Identifying a potential trigger for GVD, we found cytoplasmic accumulations of RBPs including Matrin 3 and FUS as well as stress granules in GVBs of AD patient and pR5 mouse neurons. Interestingly, we observed that GVBs containing aggregated pTau and pTDP-43 were consistently co-localized with the exosomal marker Flotillin 1 in both AD and pR5 mice. In contrast, intraneuronal 82E1-immunoreactive amyloid-ß in human AD and APP/PS1 mice only rarely co-localized with Flotillin 1-positive exosomal vesicles. We conclude that altered chaperone-mediated ER protein homeostasis and impaired autophagy manifesting in GVD are linked to both pTau and RBP accumulation and that some GVBs might be targeted to exocytosis.

Brief inhalation of nitric oxide increases resuscitation success and improves 7-day-survival after cardiac arrest in rats: a randomized controlled animal study.

INTRODUCTION: Inhaled nitric oxide (iNO) improves outcomes when given post systemic ischemia/reperfusion injury. iNO given during cardiopulmonary resuscitation (CPR) may therefore improve return of spontaneous circulation (ROSC) rates and functional outcome after cardiac arrest (CA). METHODS: Thirty male Sprague-Dawley rats were subjected to 10 minutes of CA and at least 3 minutes of CPR. Animals were randomized to receive either 0 (n = 10, Control), 20 (n = 10, 20 ppm), or 40 (n = 10, 40 ppm) ppm iNO during CPR until 30 minutes after ROSC. A neurological deficit score was assessed daily for seven days following the experiment. On day 7, brains, hearts, and blood were sampled for histological and biochemical evaluation. RESULTS: During CPR, 20 ppm iNO significantly increased diastolic arterial pressure ( CONTROL: 57 ± 5.04 mmHg; 20 ppm: 71.57 ± 57.3 mmHg, p < 0.046) and decreased time to ROSC (CONTROL: 842 ± 21 s; 20 ppm: 792 ± 5 s, (p = 0.02)). Thirty minutes following ROSC, 20 ppm iNO resulted in an increase in mean arterial pressure ( CONTROL: 83 ± 4 mmHg; 20 ppm: 98 ± 4 mmHg, p = 0.035), a less pronounced rise in lactate and inflammatory cytokine levels, and attenuated cardiac damage. Inhalation of NO at 20 ppm improved neurological outcomes in rats 2 to 7 days after CA and CPR. This translated into increases in 7 day survival ( CONTROL: 4; 20 ppm: 10; 40 ppm 6, (p ≤ 0.05 20 ppm vs CONTROL and 40 ppm). CONCLUSIONS: Our study revealed that breathing NO during CPR markedly improved resuscitation success, 7-day neurological outcomes and survival in a rat model of VF-induced cardiac arrest and CPR. These results support the beneficial effects of NO inhalation after cardiac arrest and CPR.

Inhaled nitric oxide improves transpulmonary blood flow and clinical outcomes after prolonged cardiac arrest: a large animal study.

INTRODUCTION: The probability to achieve a return of spontaneous circulation (ROSC) after cardiac arrest can be improved by optimizing circulation during cardiopulomonary resuscitation using a percutaneous left ventricular assist device (iCPR). Inhaled nitric oxide may facilitate transpulmonary blood flow during iCPR and may therefore improve organ perfusion and outcome. METHODS: Ventricular fibrillation was electrically induced in 20 anesthetized male pigs. Animals were left untreated for 10 minutes before iCPR was attempted. Subjects received either 20 ppm of inhaled nitric oxide (iNO, n = 10) or 0 ppm iNO (Control, n = 10), simultaneously started with iCPR until 5 hours following ROSC. Animals were weaned from the respirator and followed up for five days using overall performance categories (OPC) and a spatial memory task. On day six, all animals were anesthetized again, and brains were harvested for neurohistopathologic evaluation. RESULTS: All animals in both groups achieved ROSC. Administration of iNO markedly increased iCPR flow during CPR (iNO: 1.81 ± 0.30 vs CONTROL: 1.64 ± 0.51 L/min, p < 0.001), leading to significantly higher coronary perfusion pressure (CPP) during the 6 minutes of CPR (25 ± 13 vs 16 ± 6 mmHg, p = 0.002). iNO-treated animals showed significantly lower S-100 serum levels thirty minutes post ROSC (0.26 ± 0.09 vs 0.38 ± 0.15 ng/mL, p = 0.048), as well as lower blood glucose levels 120-360 minutes following ROSC. Lower S-100 serum levels were reflected by superior clinical outcome of iNO-treated animals as estimated with OPC (3 ± 2 vs. 5 ± 1, p = 0.036 on days 3 to 5). Three out of ten iNO-treated, but none of the CONTROL animals were able to successfully participate in the spatial memory task. Neurohistopathological examination of vulnerable cerebral structures revealed a trend towards less cerebral lesions in neocortex, archicortex, and striatum in iNO-treated animals compared to CONTROLs. CONCLUSIONS: In pigs resuscitated with mechanically-assisted CPR from prolonged cardiac arrest, the administration of 20 ppm iNO during and following iCPR improved transpulmonary blood flow, leading to improved clinical neurological outcomes.

Brain alterations with deep brain stimulation: New insight from a neuropathological case series.

BACKGROUND: Previous studies on human brain tissue alterations caused by deep brain stimulation described glial and reactive inflammatory changes. In the current pathoanatomical study, we extended the analysis to signs of axonal changes and the influence of concomitant disease. METHODS: Brains of 10 patients with Parkinson's disease or essential tremor and a total of 18 electrodes were systematically examined up to 7.5 y after surgery. RESULTS: In general, tissue that had long-term contact with the electrode material exhibited astrogliosis in all, T-lymphocytes in 93%, and multinucleated giant cells in 68% of patients. Immunohistochemistry showed an increase in amyloid precursor protein immunoreactive axonal swellings in the brain at the electrically active parts of the electrodes. Patients who died of septicemia showed a more severe astrogliosis and giant cell reaction than patients who died of cardiovascular events. Parkinson's disease or essential tremor did not differentially produce histopathological changes around the electrodes. CONCLUSION: Long-term electrical stimulation by deep brain stimulation causes minor axonal changes. The cause of death, but not the underlying neurological disease, affects the histopathological changes around the electrode. The findings need to be reproduced by examining larger patient subgroups.

Reducing the duration of 100% oxygen ventilation in the early reperfusion period after cardiopulmonary resuscitation decreases striatal brain damage.

PURPOSE: Previous data indicate that 100% O(2) ventilation during early reperfusion after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) increases neuronal death. However, current guidelines encourage the use of 100% O(2) during resuscitation and for an undefined period thereafter. We retrospectively analyzed data from a porcine CA model and hypothesized that prolonged hyperoxic reperfusion would be associated with increased neurohistopathological damage and impaired neurological recovery. METHODS: Fifteen male pigs underwent 8 min of CA and 5 min of CPR. After resuscitation animals were ventilated with either 100% oxygen for 60 min (hyperoxia; n=8) or 10 min (normoxia; n=7). Physiological variables were obtained at baseline and 10, 60 and 240 min after resuscitation. Daily functional performance was assessed using an established neurocognitive test in parallel to a neurological deficit score (NDS). On day 5, brains of the re-anaesthetized pigs were harvested for neurohistopathological analyses. RESULTS: At baseline there were no differences in hemodynamics and neurological status between groups. Post-arrest only PaO(2), as a result of the different inspired oxygen fractions, was significantly higher in the hyperoxia group. There was a numerical trend towards improved clinical recovery in both the NDS and the neurocognitive testing for animals exposed to 10 min of 100% oxygen. However, hyperoxic animals showed a significantly greater degree of necrotic neurons and perivascular inflammation in the striatum in comparison to normoxic animals. CONCLUSION: In this retrospective analysis prolonged hyperoxia after CA aggravated necrotic brain damage and perivascular inflammation in the striatum of pigs.

Hydrogen sulfide does not increase resuscitability in a porcine model of prolonged cardiac arrest.

Treatment options to improve resuscitability and neurological prognosis after cardiac arrest (CA) are limited. Hydrogen sulfide has demonstrated remarkable improvements in outcomes in small animal models of severe hypoxia or hemorrhage. We investigated the influence of sodium sulfide (Na2S), a liquid hydrogen sulfide donor, on resuscitability, postresuscitation hemodynamics, and neurological performance in a porcine model of prolonged CA and cardiopulmonary resuscitation. Twenty-four male pigs were instrumented with arterial and pulmonary artery catheters before 10 min of CA was induced. During resuscitation, animals were randomized to receive either high-dose (1 mg/kg; n = 8) or low-dose (0.3 mg/kg; n = 8) Na2S (IK-1001; Ikaria, Clinton, NJ) or control (saline placebo; n = 8) i.v. injection and consecutive infusion. Cardiopulmonary resuscitation was performed for 6 min before defibrillation was attempted. Hemodynamic variables were taken at baseline and 10, 30, 60, 120, and 240 min after successful resuscitation. Neurological outcome was evaluated on 4 postoperative days before brains and hearts were harvested for histopathologic analysis. No differences in hemodynamic parameters were observed at baseline. Initial resuscitability was not improved by Na2S. Animals exposed to high- and low-dose Na2S showed significantly reduced cardiac output, heart rate, and pulmonary arterial pressure compared with control animals during the early postresuscitation period. Strikingly, two of the high-dose Na2S animals died during the postresuscitation period, whereas all other animals survived. High-dose Na2S significantly decreased microglial activation in striatal areas, although this did not translate into improved neurological outcome. Although animals receiving Na2S developed higher troponin T serum levels, these differences remained insignificant. In this investigation, Na2S did not improve resuscitability but significantly compromised postresuscitation hemodynamics.

Xenon reduces neurohistopathological damage and improves the early neurological deficit after cardiac arrest in pigs.

OBJECTIVE: Treatment options to ameliorate brain damage following cardiopulmonary resuscitation from cardiac arrest are limited. DESIGN: In a porcine model, we evaluated the effects of xenon treatment on neuropathologic and functional outcomes after cardiopulmonary resuscitation. SETTING: Prospective, randomized laboratory animal study. SUBJECTS: Male pigs. INTERVENTIONS: Following successful resuscitation from 8 mins of cardiac arrest and 5 mins of cardiopulmonary resuscitation, 24 pigs were randomized to one of three groups receiving either 70% xenon for 1 or 5 hrs or untreated controls receiving 70% nitrogen. MEASUREMENTS AND MAIN RESULTS: Gas exchange, hemodynamics, and lactate and glucose levels were measured at baseline and in the postresuscitation period. On four postoperative days, neurocognitive and overall neurologic deficits were assessed before day 5, when the brains were harvested for histologic analysis of predefined regions using a semiquantitative score (0-10% = 1, 10-20% = 2, 20-50% = 3, 50-80% = 4, 80-100% = 5). No differences in gas exchange, hemodynamics, or lactate and glucose levels were observed among the groups. Animals exposed to 1 and 5 hrs of xenon showed significantly reduced scores for necrotic neurons in the putamen (1.25 +/- 0.5 and 1.25 +/- 0.5 vs. 2.5 +/- 1.2; p < 0.05), accompanied by significantly lesser scores for perivascular inflammation in putamen (0.8 +/- 0.5 and 1.1 +/- 0.8 vs. 2.1 +/- 1.1; p < 0.05) and caudate nucleus (1.0 +/- 0.8 and 0.6 +/- 0.7 vs. 2.0 +/- 1.1; p < 0.05). This resulted in improved neurocognitive and neurologic function on day 1 to 3 after cardiopulmonary resuscitation in xenon-treated animals. CONCLUSIONS: In this experimental study of cardiac arrest-induced neurologic damage, xenon conferred neurohistopathologic protection, translating in transiently improved functional outcome.

Angiomatous meningioma: a clinicopathologic study of 38 cases.

To characterize histopathological and clinical features of angiomatous meningioma, 38 cases of angiomatous meningioma, ie, meningiomas whose vascular component exceeded 50% of the total tumor area, are reported. In addition to histologic examinations, clinical characteristics as well as follow-up data were compiled. Angiomatous meningiomas constituted 2.1% of all meningiomas. Histologic signs of atypia or anaplasia were not observed in any tumor. The mean MIB-1/Ki67 proliferation index was 2.4%. Based on vessel size, two distinct histologic subtypes were identified, which differed in localization but not with regards to sex, age, presence of peritumoral edema, MIB-1/Ki67 proliferation index, or progesterone receptor status. In patients with gross tumor resection, no recurrences occurred. To conclude, angiomatous meningiomas share histologic and clinical features of benign meningiomas. Since all angiomatous meningiomas examined here were grade 1 tumors, the diagnosis of angiomatous meningioma may have prognostic implications. Therefore, the existence of this rare subgroup of meningioma appears justified.