Raising serum uric acid with a uricase inhibitor worsens PKD in rat and mouse models.

Humans are predisposed to gout because they lack uricase that converts uric acid to allantoin. Rodents have uricase, resulting in low basal serum uric acid. A uricase inhibitor raises serum uric acid in rodents. There were two aims of the study in polycystic kidney disease (PKD): 1) to determine whether increasing serum uric acid with the uricase inhibitor, oxonic acid, resulted in faster cyst growth and 2) to determine whether treatment with the xanthine oxidase inhibitor, oxypurinol, reduced the cyst growth caused by oxonic acid. Orthologous models of human PKD were used: PCK rats, a polycystic kidney and hepatic disease 1 (Pkhd1) gene model of autosomal recessive PKD (ARPKD) and Pkd1RC/RC mice, a hypomorphic Pkd1 gene model. In PCK rats and Pkd1RC/RC mice, oxonic acid resulted in a significant increase in serum uric acid, kidney weight, and cyst index. Mechanisms of increased cyst growth that were investigated were proinflammatory cytokines, the inflammasome, and crystal deposition in the kidney. Oxonic acid resulted in an increase in proinflammatory cytokines in the serum and kidney in Pkd1RC/RC mice. Oxonic acid did not cause activation of the inflammasome or uric acid crystal deposition in the kidney. In Pkd1RC/RC male and female mice analyzed together, oxypurinol decreased the oxonic acid-induced increase in cyst index. In summary, increasing serum uric acid by inhibiting uricase with oxonic acid results in an increase in kidney weight and cyst index in PCK rats and Pkd1RC/RC mice. The effect is independent of inflammasome activation or crystal deposition in the kidney.NEW & NOTEWORTHY This is the first reported study of uric acid measurements and xanthine oxidase inhibition in polycystic kidney disease (PKD) rodents. Raising serum uric acid with a uricase inhibitor resulted in increased kidney weight and cyst index in Pkd1RC/RC mice and PCK rats, elevated levels of proinflammatory cytokines in the serum and kidney in Pkd1RC/RC mice, and no uric acid crystal deposition or activation of the caspase-1 inflammasome in the kidney.

The evaluation of miR-1181 and miR-4314 as serum microRNA biomarkers for epithelial ovarian cancer diagnosis and prognosis.

AIM: Epithelial ovarian cancer (EOC) is the most ominous tumor of gynecological cancers due to its poor early detection rate and unfavorable prognosis. To date, there is no reliable screening method for the diagnosis of ovarian cancer at an early stage. MiRNAs are small non-coding RNA molecules, and their main function is to regulate gene expression. The present study compared the serum miR-1181 and miR-4314 levels in patients with EOC and healthy controls to measure the diagnostic and prognostic value as candidate biomarkers. MATERIALS AND METHODS: We collected serum samples from a total of 135 participants (69 patients with EOC and 66 healthy controls). Relative expressions of miR-1181 and miR-4314 were measured by quantitative real-time polymerase chain reaction assay (qPCR). RESULTS: The present study revealed that both serum miR-1181 and miR-4314 levels in patients with EOC were significantly increased compared to healthy controls for each marker. In addition, there was a significant relationship between miR-1181 and miR-4314 overexpressions and the stage and prognosis of the disease. Finally, patients with high expression levels of miR-1181 and miR-4314 had significantly shorter survival rates than those with low expression levels. CONCLUSION: The current study proposed that serum miR-1181 and miR-4314 could discriminate the EOC patients from healthy controls. In addition, both miR-1181 and miR-4314 may be predictive biomarkers for ovarian cancer prognosis. Further studies are needed to confirm the findings of the present study.

Metformin does not slow cyst growth in the PCK rat model of polycystic kidney disease.

Metformin (MET) has the potential to activate p-AMPK and block mTORC1-induced proliferation of tubular cells in PKD kidneys. The aim of this study was to determine the effects of MET on cyst growth, kidney function, AMPK and mTOR signaling, and lactate levels in male PCK rats, a Pkhd1 gene mutation model of human autosomal recessive polycystic kidney disease (ARPKD). MET 300 mg/kg/day IP from days 28 to 84 of age resulted in a mean serum metformin level that was 10 times the upper limit of therapeutic, no effect on cyst indices, nephrotoxicity, and increased serum lactate. MET 150 mg/kg resulted in a therapeutic serum metformin level but had no effect on kidney weight, cyst indices, kidney function, or mTOR and autophagy proteins. In summary, a standard dose of MET was ineffective in reducing PKD, did not activate p-AMPK or suppress mTOR and the higher dose resulted in increased lactate levels and nephrotoxicity. In conclusion, the study dampens enthusiasm for human studies of MET in PKD. Doubling the metformin dose resulted in a 10-fold increase in mean blood levels and toxicity suggesting that the dosage range between therapeutic and toxic is narrow.

BIIB021, an orally available and small-molecule inhibitor of HSP90, activates intrinsic apoptotic pathway in human cervical adenocarcinoma cell line (HeLa).

OBJECTIVE: Heat shock protein 90 (HSP90) is a highly conserved ATP-dependent chaperone protein that plays a vital role in tumorigenesis. This study aims to investigate the apoptosis inducer role of BIIB021 (orally available HSP90 inhibitors) compound via inhibition of HSP90 activity in the human cervical cancer cell line (HeLa). PATIENTS AND METHODS: The anticancer potential of BIIB021 was determined by XTT [2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)] cell proliferation assay against the human cervical cancer cell line (HeLa). ATPase and luciferase aggregation assays were carried out to detect the HSP90 inhibitor potential of BIIB021. To determine the antiproliferative mechanism of the BIIB021, the expression level of the pro-apoptotic and antiapoptotic markers was determined by reverse transcription polymerase chain reaction (RT-PCR) and ELISA experiments. RESULTS: BIIB021 exhibited a cytotoxic effect on HeLa cell proliferation and the inhibitory concentration (IC)50 dose of BIIB021 was found to be 14.79 nM at 48 h. BIIB021 decreased the ATP hydrolysis rate of HSP90 and blocked the refolding of the desaturated luciferase in the presence of ATP. To understand the antiproliferative mechanism of the BIIB021 in HeLa cells, the mRNA and protein expression levels of the apoptotic markers [BCL-2 associated X (BAX), B-cell lymphoma 2 (BCL-2), cytochrome-c (CYT-c), and caspase-3 (CAS-3)] were determined by RT-PCR and ELISA experiments. The results obtained indicated that BIIB021 decreased BCL-2 levels and increased BAX, CYT-c, and CAS-3 levels in human cervical cancer cells. CONCLUSIONS: These results confirmed that BIIB021 inhibited the chaperone activity of HSP90, resulting in anti-proliferating effects in cervical cancer cells via the induction of the intrinsic apoptotic pathways.

Choice between decision-making strategies in human route-following.

To follow a prescribed route, we must decide which way to turn at intersections. To do so, we can memorize either the serial order of directions or the associations between spatial cues and directions ("at the drug store, turn left"). Here, we investigate which of these two strategies is used if both are available. In Task S, all intersections looked exactly alike, and participants therefore had to use the serial order strategy to decide which way their route continued. In Task SA, each intersection displayed a unique spatial cue, and participants therefore could use either strategy. In Task A, each intersection displayed a unique cue, but the serial order of cues varied between trips, and participants therefore had to use the associative cue strategy. We found that route-following accuracy increased from trip to trip, was higher on routes with 12 rather than 18 intersections, and was higher on Task SA than on the other two tasks, both with 12 and with 18 intersections. Furthermore, participants on Task SA acquired substantial knowledge about the serial order of directions as well as about cue-direction associations, both with 12 and with 18 intersections. From this we conclude that, when both strategies were available, participants did not pick the better one but rather used both. This represents dual encoding, a phenomenon previously described for more elementary memory tasks. We further conclude that dual encoding may be implemented even if the memory load is not very high (i.e., even with only 12 intersections).

The Pathophysiology of Left Ventricular Hypertrophy, beyond Hypertension, in Autosomal Dominant Polycystic Kidney Disease.

Heart disease is one of the leading causes of death in autosomal dominant polycystic kidney disease (ADPKD) patients. Left ventricular hypertrophy (LVH) is an early and severe complication in ADPKD patients. Two decades ago, the prevalence of LVH on echocardiography in hypertensive ADPKD patients was shown to be as high as 46%. Recent studies using cardiac magnetic resonance imaging have shown that the prevalence of LVH in ADPKD patients may be lower. The true prevalence of LVH in ADPKD patients is controversial. There is evidence that factors other than hypertension contribute to LVH in ADPKD patients. Studies have shown that young normotensive ADPKD adults and children have a higher left ventricular mass index compared to controls and that the prevalence of LVH is high in patients with ADPKD whose blood pressure is well controlled. Polycystin-1 (PC-1) and polycystin-2 (PC-2) control intracellular signaling pathways that can influence cardiac function. Perturbations of PC-1 or PC-2 in the heart can lead to profound changes in cardiac structure and function independently of kidney function or blood pressure. PC-1 can influence mammalian target of rapamycin and mitophagy and PC-2 can influence autophagy, processes that play a role in LVH. Polymorphisms in the angiotensin-converting enzyme gene may play a role in LVH in ADPKD. This review will detail the pathophysiology of LVH, beyond hypertension, in ADPKD.

The effect of post-auricular canal wall down mastoidectomy on the position of the auricle.

OBJECTIVE: This study aimed to investigate the effect of surgical incision on the auricle position in patients undergoing canal wall down mastoidectomy to treat chronic otitis media. METHODS: Thirty-four patients who had undergone canal wall down mastoidectomy with a post-auricular incision approach were included in the study. Patients who had a previous auricle deformity, who underwent limited mastoidectomy surgery or mastoid obliteration, or who were younger than 18 years of age were excluded. The distances of the upper and middle parts of the auricle to the mastoid were measured. RESULTS: Measurements in the first post-operative year were found to be 13.15 ± 3.59 mm in the upper region and 16.29 ± 5.00 mm in the middle region. It was observed that the auricle was approaching the mastoid area in both regions. CONCLUSION: In patients undergoing radical mastoidectomy, the distance between the auricle and the mastoid may decrease, leading to narrowing of the auriculo-cephalic angle.

Simulation-based training improves process times in acute stroke care (STREAM).

BACKGROUND: The objective of the STREAM Trial was to evaluate the effect of simulation training on process times in acute stroke care. METHODS: The multicenter prospective interventional STREAM Trial was conducted between 10/2017 and 04/2019 at seven tertiary care neurocenters in Germany with a pre- and post-interventional observation phase. We recorded patient characteristics, acute stroke care process times, stroke team composition and simulation experience for consecutive direct-to-center patients receiving intravenous thrombolysis (IVT) and/or endovascular therapy (EVT). The intervention consisted of a composite intervention centered around stroke-specific in situ simulation training. Primary outcome measure was the 'door-to-needle' time (DTN) for IVT. Secondary outcome measures included process times of EVT and measures taken to streamline the pre-existing treatment algorithm. RESULTS: The effect of the STREAM intervention on the process times of all acute stroke operations was neutral. However, secondary analyses showed a DTN reduction of 5 min from 38 min pre-intervention (interquartile range [IQR] 25-43 min) to 33 min (IQR 23-39 min, p = 0.03) post-intervention achieved by simulation-experienced stroke teams. Concerning EVT, we found significantly shorter door-to-groin times in patients who were treated by teams with simulation experience as compared to simulation-naive teams in the post-interventional phase (-21 min, simulation-naive: 95 min, IQR 69-111 vs. simulation-experienced: 74 min, IQR 51-92, p = 0.04). CONCLUSION: An intervention combining workflow refinement and simulation-based stroke team training has the potential to improve process times in acute stroke care.

Prolongation of Neoadjuvant Chemotherapy before Surgery: Seeking the Optimal Number of Cycles in Serous Ovarian Cancer.

AIM: The optimal number of neoadjuvant chemotherapy (NACT) cycles is unclear in epithelial ovarian cancer. Our study aimed to evaluate the effect of the number of NACT cycles before interval debulking surgery on survival. METHODS: Data of 221 patients with advanced-stage serous epithelial ovarian cancer (EOC) were retrospectively evaluated. The patients were divided into groups as who received 3 cycles of NACT (group A), 4-5 cycles of NACT (group B), and 6 cycles of NACT (group C). RESULTS: There were 67 (30%) patients in group A, 70 (32%) in group B, and 84 (38%) in group C. Median overall survival (OS) was 61 (range 43-79) months for group A, 44 (range 36-52) months for group B, and 39 (range 27-50) months for group C. In addition, median disease-free survival (DFS) was 23.1 (range 8.5-32.1) months for group A, 19.2 (range 10.1-28.4) months for group B, and 21.5 (range 16-27) months for group C. Patients receiving >3 NACT cycles had worse OS than patients who received 3 NACT cycles (for group A vs. B, p = 0.018; for group A vs. C, p = 0.049). However, in terms of DFS, patients receiving 3 NACT cycles had no statistically significant difference compared to patients who received >3 NACT cycles. CONCLUSIONS: Patients with advanced-stage serous EOC who received more than 3 cycles of NACT had poor OS. However, there was no statistical difference in terms of DFS. In addition, >3 cycles of NACT did not increase the probability of achieving complete cytoreduction at the time of surgery.

Reconstruction of ear canal wall with superior pedicled composite multi-fractured osteoperiosteal flap: a new technique and preliminary outcomes.

OBJECTIVE: This study evaluated the functional results of the superior pedicled composite multi-fractured osteoperiosteal flap technique. This method is a novel technique for the reconstruction of the external auditory canal. The study also examined the effect of the superior pedicled composite multi-fractured osteoperiosteal flap technique on patients' disease-related quality of life. METHOD: A total of 37 patients who underwent the superior pedicled composite multi-fractured osteoperiosteal flap technique were enrolled in the study. Their functional hearing results and disease-related quality of life scores were evaluated. RESULTS: A significant improvement was observed in the patients' hearing scores at the post-operative sixth month relative to the pre-operative period, and the patients' disease-related quality of life increased significantly. CONCLUSION: The superior pedicled composite multi-fractured osteoperiosteal flap method can be safely used, especially in patients undergoing retrograde mastoidectomy because of limited cholesteatoma. This method contributes to improving patients' hearing levels and disease-related quality of life.

Effect of internal carotid artery aberrations on the distance between styloid process and carotid artery / Efecto de las variaciones de la arteria carótida interna en la distancia entre el proceso estiloides y la arteria carótida

SUMMARY: The objective of this study was to evaluate the role of the variations of carotid artery course on the relationship between styloid process (SP) and internal carotid artery (ICA). Carotid CT angiography scans of 170 patients were retrospectively evaluated. The variability of the course of ICA were classified. The length and medial angulation of the SP were measured on coronal 3D images. On axial images, the shortest distance between the bone edge of the SP and ICA were measured. The distance between SP and ICA among the course patterns of carotid artery were compared statistically. In the comparison of distances between SP and ICA with respect to the course of ICA, the difference between straight and curving (p <0.001) was statistically significant. Curving caused the separation of ICA and SP. The highest and the shortest distance was at the curving and coiling group, respectively. We found that SP-ICA distance has a positive and negative correlation with SP angle (p<0.001) and SP length (p<0.001), respectively. The course of ICA is one of the major determinants affecting the relationship of ICA and SP. The curving pattern of ICA has a tendency to increase the distance between SP and ICA.

RESUMEN: El objetivo de este estudio fue evaluar el rol de las variaciones que tiene el curso de la arteria carótida en la relación entre el proceso estiloides (PE) y la arteria carótida interna (ACI). Se evaluaron retrospectivamente angiografías por tomografía computarizada carotídea de 170 pacientes. Se clasificó la variabilidad del curso de ACI. Se midieron en imágenes coronales y en 3D la longitud y la angulación medial del PE. En las imágenes axiales, se midió la distancia más corta entre el margen del PE y la ACI. Se comparó estadísticamente la distancia entre PE y la ACI entre los patrones de trayecto de la arteria carótida. La comparación de las distancias entre PE y la ACI respecto al curso de ACI, fue estadísticamente significativa, siendo la diferencia entre arterias recta y curva (p <0,001). La arteria curva provocó la separación de la ACI y del PE. Las mayores y menores distancias estaban en el grupo de arterias curvas y enrolladas, respectivamente. La distancia PE-ACI tiene una correlación positiva y negativa con el ángulo PE (p <0,001) y la longitud del PE (p <0,001), respectivamente. El curso de la arteria carótida interna es uno de los principales determinantes que afectan la relación con el proceso estiloides. El patrón de curva de la ACI tiende a aumentar la distancia entre PE y la propia arteria arteria.

Osteoclastic activity in chronic otitis media with cholesteatoma-related bone destruction.

BACKGROUND: Cholesteatoma-related bone destruction is the cause of many complications due to chronic otitis media. This study aimed to evaluate osteoclastic activity in cholesteatoma-related bone destruction using tartrate-resistant acid phosphatase 5b, an enzyme specific to osteoclastic activity. METHOD: Seventy-two patients diagnosed with chronic otitis media were included in this study and were divided into two groups: with and without bone destruction. The blood serum and tissue tartrate-resistant acid phosphatase 5b levels from both groups were compared. RESULTS: There were no significant differences in the level of serum enzymes between both groups. However, in tissue samples, tartrate-resistant acid phosphatase 5b levels were significantly lower in the bone destruction group than the group without bone destruction. CONCLUSION: This study determined that the level of tartrate-resistant acid phosphatase 5b, a specific enzyme for osteoclastic activity in cholesteatoma-related bone destruction, is locally decreased. This data suggests that osteoclastic activity may decrease in cholesteatoma-related bone destruction. However, further experimental and clinical studies are required to clarify this highly complex mechanism.

Risk Factors of Procedural Complications Related to Woven EndoBridge (WEB) Embolization of Intracranial Aneurysms.

PURPOSE: The Woven EndoBridge (WEB) device has been proven to be a safe and efficient endovascular treatment option for wide-necked bifurcation aneurysms. The study aimed to evaluate the incidence and risk factors of procedural complications related to WEB embolization of ruptured and unruptured intracranial aneurysms. METHODS: This was a multicenter, observational study of consecutive patients with ruptured and unruptured aneurysms who were treated with the WEB at three German tertiary care centers between May 2011 and February 2018. Patient characteristics, anatomical details and procedural aspects were retrospectively collected and the impact on procedure-related complications was evaluated. RESULTS: Among 120 patients (mean age 58.5 ± 11.9 years) with 120 aneurysms (mean size: 8.5 ± 4.5 mm), WEB implantation was successful in 112 patients (93.3%). The rates for overall and symptomatic complications were 11.7% and 5.0%, respectively. At 6­month follow-up device-related morbidity was 1.2% among unruptured aneurysms and 2.6% among ruptured aneurysms. In the univariate analysis, a lower aspect ratio (p = 0.04) and an increased width-to-height ratio (p = 0.03) were significant risk factors for procedural complications. CONCLUSION: The results of this study confirmed the WEB to be a safe treatment option, which is associated with low complication rates and minimal morbidity. Complications tended to occur more often in aneurysms with an unfavorable ratio between aneurysm height and aneurysm/neck width.

In the Eye of the Storm: Immune-mediated Toxicities Associated With CAR-T Cell Therapy.

The success of chimeric antigen receptor (CAR)-T cell therapy with impressive response rates in hematologic malignancies but also promising data in solid tumors came along with the cognition of unexpected, potentially life-threatening immune-mediated toxicities, namely the cytokine release syndrome (CRS) and neurotoxicity recently referred to as "immune effector cell-associated neurotoxicity syndrome" (ICANS). These toxicities require urgent diagnostic and therapeutic interventions and targeted modulation of key cytokine pathways represents the mainstay of CRS treatment. However, as the underlying mechanisms of ICANS are not well understood, treatment options remain limited and further investigation is warranted. Importantly, after the recent market approval of 2 CAR-T cell constructs, the application of CAR-T cells will expand to nonacademic centers with limited experience in the management of CAR-T cell-associated toxicities. Here, we review the current evidence of CRS and ICANS pathophysiology, diagnostics, and treatment.

Level of education mitigates the impact of tau pathology on neuronal function.

PURPOSE: Using PET imaging in a group of patients with Alzheimer's disease (AD), we investigated whether level of education, a proxy for resilience, mitigates the harmful impact of tau pathology on neuronal function. METHODS: We included 38 patients with mild-to-moderate AD (mean age 67 ± 7 years, mean MMSE score 24 ± 4, mean years of education 14 ± 4; 20 men, 18 women) in whom a [18F]AV-1451 scan (a measure of tau pathology) and an [18F]FDG scan (a measure of neuronal function) were available. The preprocessed PET scans were z-transformed using templates for [18F]AV-1451 and [18F]FDG from healthy controls, and subsequently thresholded at a z-score of ≥3.0, representing an one-tailed p value of 0.001. Next, three volumes were computed in each patient: the tau-specific volume (tau pathology without neuronal dysfunction), the FDG-specific volume (neuronal dysfunction without tau pathology), and the overlap volume (tau pathology and neuronal dysfunction). Mean z-scores and volumes were extracted and used as dependent variables in regression analysis with years of education as predictor, and age and MMSE score as covariates. RESULTS: Years of education were positively associated with tau-specific volume (ß = 0.362, p = 0.022), suggesting a lower impact of tau pathology on neuronal function in patients with higher levels of education. Concomitantly, level of education was positively related to tau burden in the overlap volume (ß = 0.303, p = 0.036) implying that with higher levels of education more tau pathology is necessary to induce neuronal dysfunction. CONCLUSION: In patients with higher levels of education, tau pathology is less paralleled by regional and remote neuronal dysfunction. The data suggest that early life-time factors such as level of education support resilience mechanisms, which ameliorate AD-related effects later in life.

Factors affecting the return to work of total hip arthroplasty due to of developmental hip dysplasia in in young patients.

INTRODUCTION: The aim of this study was to examine the factors affecting return to work after Total hip arthroplasty (THA) applied for coxarthrosis due to developmental hip dysplasia (DDH). METHODS: The study included 51 patients aged <60 years in the period 2004-2010. The demographic information was recorded for all patients and the pre-postoperative Modified Harris score, EQ-5D, EQ-5D VAS and Grimby activity score. With an evaluation of the current employment status at the final follow-up examination. RESULTS: Preoperatively, 21 patients were employed, 16 were unemployed and 14 were housewives, none of whom were able to perform housework tasks. Postoperatively, 30 patients were employed and 10 were unemployed. One of the previously employed patients decided preoperatively to retire and was therefore not employed postoperatively. Of the 14 housewives, 9 were able to undertake the housework themselves postoperatively. The mean time of return to work was 13.4 weeks. Factors affecting finding work postoperatively were determined to be body mass index, National Occupational Level, whether or not osteotomy was applied and the preoperative duration of unemployment. CONCLUSIONS: As coxarthrosis associated with DDH develops earlier than primary coxarthrosis, these patients undergo surgery at a younger age and the vast majority are of working age. THA applied for coxarthrosis on the basis of DDH enables most patients to return to their preoperative work and offers the opportunity of finding work to some of those who were unemployed. This increases the contribution of these patients to the national economy.

Networks of tau distribution in Alzheimer's disease.

See Whitwell (doi:10.1093/brain/awy001) for a scientific commentary on this article.A stereotypical anatomical propagation of tau pathology has been described in Alzheimer's disease. According to recent concepts (network degeneration hypothesis), this propagation is thought to be indicative of misfolded tau proteins possibly spreading along functional networks. If true, tau pathology accumulation should correlate in functionally connected brain regions. Therefore, we examined whether independent components could be identified in the distribution pattern of in vivo tau pathology and whether these components correspond with specific functional connectivity networks. Twenty-two 18F-AV-1451 PET scans of patients with amnestic Alzheimer's disease (mean age = 66.00 ± 7.22 years, 14 males/eight females) were spatially normalized, intensity standardized to the cerebellum, and z-transformed using the mean and deviation image of a healthy control sample to assess Alzheimer's disease-related tau pathology. First, to detect distinct tau pathology networks, the deviation maps were subjected to an independent component analysis. Second, to investigate if regions of high tau burden are associated with functional connectivity networks, we extracted the region with the maximum z-value in each of the generated tau pathology networks and used them as seeds in a subsequent resting-state functional MRI analysis, conducted in a group of healthy adults (n = 26) who were part of the 1000 Functional Connectomes Project. Third, to examine if tau pathology co-localizes with functional connectivity networks, we quantified the spatial overlap between the seed-based networks and the corresponding tau pathology network by calculating the Dice similarity coefficient. Additionally, we assessed if the tau-dependent seed-based networks correspond with known functional resting-state networks. Finally, we examined the relevance of the identified components in regard to the neuropathological Braak stages. We identified 10 independently coherent tau pathology networks with the majority showing a symmetrical bi-hemispheric expansion and coinciding with highly functionally connected brain regions such as the precuneus and cingulate cortex. A fair-to-moderate overlap was observed between the tau pathology networks and corresponding seed-based networks (Dice range: 0.13-0.57), which in turn resembled known resting-state networks, particularly the default mode network (Dice range: 0.42-0.56). Moreover, greater tau burden in the tau pathology networks was associated with more advanced Braak stages. Using the data-driven approach of an independent component analysis, we observed a set of independently coherent tau pathology networks in Alzheimer's disease, which were associated with disease progression and coincided with functional networks previously reported to be impaired in Alzheimer's disease. Together, our results provide novel information regarding the impact of tau pathology networks on the mechanistic pathway of Alzheimer's disease.

Thrombus Enhancement Is a Predictor of Clinical Outcome in Acute Ischemic Stroke after Mechanical Thrombectomy.

BACKGROUND: Ex vivo computed tomography (CT) studies of artificial blood thrombi showed that contrast enhancement (CE) is determined by fibrin-content, while unenhanced density is associated with red blood cells. Thus, the present study investigates patient outcome in association with combined thrombus density measures in native and contrast-enhanced CT (CECT) of acute ischemic stroke patients. METHODS: This retrospective study includes 137 patients with M1 occlusions treated by mechanical thrombectomy (MT) between 2010 and 2016. Clinical outcome was determined with modified Rankin Scale (mRS) at 90 days. Differentiation of complete and incomplete large vessel occlusion (CLVO/ILVO) was based on CT and angiography. Two blinded readers classified blood thrombi based on native non-enhanced CT (NECT) as (a) hypo-, (b) iso-, and (c) hyperdense and in CECT angio measurements as (d) not-enhancing, (e) intermediate and (f) enhancing. To make sure that the mean is not represented in any of the maximum/minimum groups, thresholds in both cases were selected in a way that all values within one SD around the mean value form the isodense/intermediate group. In addition, the CE per se was correlated with the outcome. Correlations between imaging and clinical scales were performed with Spearman's Rho. For the group testing Pearson chi-square test, Mann-Whitney U, as well parametric and nonparametric one-factor ANOVA "Kruskal-Wallis" test including Bonferroni correction for multiple tests ware used. RESULTS: Twenty-three patients with ILVO (16.8%) differed significantly from patients with CLVO in mRS at admission (median 4 vs. 5) and after 90 days (median 1 vs. 4; p < 0.05) and thus were excluded. In the ILVO cohort, the classification according to NECT did not show statistical difference between hypo-, iso- and hyperdense CLVOs in regard to outcome. Classification of CLVOs according to CECT allowed an outcome prediction between the intermediate (median 3) and enhancing group (median 5) and between the enhancing and non-enhancing group (median 3; both p < 0.05) with a correlation of 291 between CE and higher mRS after 90 days (p < 0.005). CONCLUSIONS: CE of thrombi - especially in a range from over 18.4 to 40.35 Hounsfield Units - is an independent predictor of poor clinical outcome in patients undergoing MT due to acute middle cerebral artery occlusion.

Functional Disintegration of the Default Mode Network in Prodromal Alzheimer's Disease.

Neurodegenerative brain changes can affect the functional connectivity strength between nodes of the default-mode network (DMN), which may underlie changes in cognitive performance. It remains unclear how the functional connectivity strength of DMN nodes differs from healthy to pathological aging and whether these changes are cognitively relevant. We used resting-state functional magnetic resonance imaging to investigate the functional connectivity strength across five DMN nodes in 25 healthy controls (HC), 28 subjective cognitive decline (SCD) participants, and 25 prodromal Alzheimer's disease (AD) patients. After identifying the ventral medial prefrontal cortex (vmPFC), posterior cingulate cortex (PCC), retrosplenial cortex (RSC), inferior parietal lobule, and the hippocampus we investigated the functional strength between DMN nodes using temporal network modeling. Functional coupling of the vmPFC and PCC in prodromal AD patients was disrupted. This vmPFC-PCC coupling correlated positively with memory performance in prodromal AD. Furthermore, the hippocampus de-coupled from posterior DMN nodes in SCD and prodromal AD patients. There was no coupling between the hippocampus and the anterior DMN. Additional mediation analyses indicated that the RSC enables communication between the hippocampus and DMN regions in HC but none of the other two groups. These results suggest an anterior-posterior disconnection and a hippocampal de-coupling from posterior DMN nodes with disease progression. Hippocampal de-coupling already occurring in SCD may provide valuable information for the development of a functional biomarker.