Increased retention of tau PET ligand [18F]-AV1451 in Alzheimer's Disease Psychosis.

Psychosis in Alzheimer's disease (AD) represents a distinct disease subtype with a more rapid progression of illness evidenced by an increased velocity of cognitive decline and a hastened mortality. Previous biomarker and post-mortem studies have implicated tau neuropathology as a possible mediator of the accelerated decline in AD psychosis. Tau positron emission tomography (PET) neuroimaging provides the opportunity to evaluate tau pathology in-vivo, so that clinical symptomatology can be correlated with disease pathology. [18F]-AV1451 (Flortaucipir) is a PET ligand with high affinity for insoluble paired-helical filaments (PHFs) of hyperphosphorylated tau. In order to determine whether the development of psychosis and worsened prognosis in AD is associated with an increased burden of tau pathology that can be identified with tau imaging, we identified subjects within the Alzheimer's disease neuroimaging initiative (ADNI) who had [18F]-AV1451 imaging at baseline and became psychotic over the course of the study (N = 17) and matched them 1:3 for gender, age, and education to subjects who had [18F]-AV1451 imaging at baseline and did not become psychotic (N = 50). We compared baseline [18F]-AV1451 retention, in addition to cognitive and functional baseline and longitudinal change, in those who became psychotic over the course of participation in ADNI with those who did not. Results suggest that increases in tau pathology in frontal, medial temporal, and occipital cortices, visualized with [18F]-AV1451 binding, are associated with psychosis and a more rapid cognitive and functional decline.

Impact of Home-Delivered Meals on Nutrition Status and Nutrient Intake among Older Adults in Central Texas.

OBJECTIVE: This study aimed to measure changes in nutrition risk and nutrient intake after older adults received home-delivered meals (HDM) for 3 months. DESIGN: This study used a pre-posttest study design, with data collected before and after 3 months of HDM services. SETTING: Two HDM programs that serve the metropolitan areas of Austin and San Antonio, Texas. PARTICIPANTS: Study participants were aged 60 years or older, without dementia or terminal illness, and receiving HDM in Austin, Texas and San Antonio, Texas for 3 months. MEASUREMENTS: The Nutrition Screening Initiative (NSI) and Mini Nutrition Assessment-Short Form (MNA-SF) were used to assess nutritional risk. The National Cancer Institute Diet History Questionnaire II (DHQ II) was used to assess nutrient intake over the past month. RESULTS: After receiving 3 months of HDM, nutrition status significantly improved as measured by the NSI and MNA-SF. More participants met or exceeded the recommended dietary allowances (RDA) for magnesium and zinc after receiving HDM compared to before receiving HDM. Dietary supplement intake was associated with a higher nutritional risk. CONCLUSION: Improvements in nutrition status were found after 3 months of receiving HDM, whereas intake of most nutrients did not change significantly. Results of this study provide further evidence that HDM can reduce nutritional risk of older adults, and may inform HDM programs on the differences of NSI and/or MNA-SF to assess nutritional risk of clients.

Safety and efficacy of endoscopic spray cryotherapy for esophageal cancer.

Although surgery is traditionally the standard of care for esophageal cancer, esophagectomy carries significant morbidity. Alternative endoscopic therapies are needed for patients who are not candidates for conventional treatment. The objective of this study is to assess the safety, efficacy, and tolerability of spray cryotherapy of esophageal adenocarcinoma. This study includes patients with esophageal adenocarcinoma who had failed or were not candidates for conventional therapy enrolled retrospectively and prospectively in an open-label registry and patients in a retrospective cohort from 11 academic and community practices. Endoscopic spray cryotherapy was performed until biopsy proven local tumor eradication or until treatment was halted due to progression of disease, patient withdrawal or comorbidities. Eighty-eight patients with esophageal adenocarcinoma (median age 76, 80.7% male, mean length 5.1 cm) underwent 359 treatments (mean 4.4 per patient). Tumor stages included 39 with T1a, 25 with T1b, 9 with unspecified T1, and 15 with T2. Eighty-six patients completed treatment with complete response of intraluminal disease in 55.8%, including complete response in 76.3% for T1a, 45.8% for T1b, 66.2% for all T1, and 6.7% for T2. Mean follow-up was 18.4 months. There were no deaths or perforations related to spray cryotherapy. Strictures developed in 12 of 88 patients (13.6%) but were present before spray cryotherapy in 3 of 12. This study suggests that endoscopic spray cryotherapy is a safe, well-tolerated, and effective treatment option for early esophageal adenocarcinoma.

Safety and efficacy of endoscopic spray cryotherapy for Barrett's dysplasia: results of the National Cryospray Registry.

Retrospective series have shown the efficacy of endoscopic spray cryotherapy in eradicating high-grade dysplasia (HGD) in Barrett's esophagus (BE); however, prospective data are lacking, and efficacy for low-grade dysplasia (LGD) is unclear. The aim of this study was to assess the efficacy and safety of spray cryotherapy in patients with LGD or HGD. A multicenter, prospective open-label registry enrolled patients with dysplastic BE. Spray cryotherapy was performed every 2-3 months until there was no endoscopic evidence of BE and no histological evidence of dysplasia, followed by surveillance endoscopies up to 2 years. Primary outcome measures were complete eradication of dysplasia (CE-D) and complete eradication of all intestinal metaplasia (CE-IM). Ninety-six subjects with Barrett's dysplasia (67% HGD; 65% long-segment BE; mean length 4.5 cm) underwent 321 treatments (mean 3.3 per subject). Mean age was 67 years, 83% were male. Eighty patients (83%) completed treatment with follow-up endoscopy (mean duration 21 months). In patients with LGD, rate of CE-D was 91% (21/23) and rate of CE-IM was 61% (14/23). In HGD, CE-D rate was 81% (46/57) and CE-IM was 65% (37/57). In patients with short-segment BE (SSBE) with any dysplasia, CE-D was achieved in 97% (30/31) and CE-IM in 77% (24/31). There were no esophageal perforations or related deaths. One subject developed a stricture, which did not require dilation. One patient was hospitalized for bleeding in the setting of non-steroidal anti-inflammatory drug use. In the largest prospective cohort to date, data suggest endoscopic spray cryotherapy is a safe and effective modality for eradication of BE with LGD or HGD, particularly with SSBE.

Pathogenic tau species drive a psychosis-like phenotype in a mouse model of Alzheimer's disease.

Psychotic Alzheimer's disease (AD+P) is a rapidly progressive variant of AD associated with an increased burden of frontal tau pathology that affects up to 50% of those with AD, and is observed more commonly in females. To date, there are no safe and effective medication interventions with an indication for treatment in this condition, and there has been only very limited exploration of potential animal models for pre-clinical drug development. Pathogenic tau is over represented in the frontal cortex in AD+P, especially in females. In order to develop a candidate animal model of AD+P, we employed a tau mouse model with a heavy burden of frontal tau pathology, the rTg(tauP301L)4510 mouse, hereafter termed rTg4510. We explored deficits of prepulse inhibition of acoustic startle (PPI), a model of psychosis in rodents, and the correlation between pathogenic phospho-tau species associated with AD+P and PPI deficits in female mice. We found that female rTg4510 mice exhibit increasing PPI deficits relative to littermate controls from 4.5 to 5.5 months of age, and that these deficits are driven by insoluble fractions of the phospho-tau species pSer396/404, pSer202, and pThr231 found to be associated with human AD+P. This preliminary data suggests the utility of the rTg4510 mouse as a candidate disease model of human female AD+P. Further work expanded to include both genders and other behavioral outcome measures relevant to AD+P is necessary.

Eosinophilic infiltration of the esophagus following endoscopic ablation of Barrett's neoplasia.

To assess the incidence of esophageal intra-epithelial eosinophilic infiltration following endoscopic ablation of Barrett's esophagus (BE), a retrospective study of consecutive cases of endoscopic ablation of BE with dysplasia or cancer using radiofrequency ablation (RFA) and spray cryotherapy at two centers in the United States was performed. Post-ablation eosinophilia was defined as ≥ 5 eosinophils per high power field during post-treatment surveillance. Twenty of 122 patients (16%) undergoing ablation developed esophageal eosinophilia after ablation, including 8/77 (10%) treated with RFA and 12/44 (27%) treated with cryotherapy. No patient had clinical or endoscopic findings of or risk factors for eosinophilic esophagitis. Esophageal eosinophilia persisted in 30% over a median of 20.2 months. On multivariate analysis, post-ablation eosinophilia was independently associated with increasing BE segment length (adjusted odds ratio 1.46 for every 2-cm increase, 95% confidence interval 1.24-1.71) and cryotherapy as the ablation modality (adjusted odds ratio 5.23, 95% confidence interval 1.67-16.39). Esophageal eosinophilic infiltration after endoscopic ablation with RFA and cryotherapy is common and is associated with the BE segment length and treatment modality. The clinical significance of post-ablation eosinophilia is unclear.

Recurrent disease following endoscopic ablation of Barrett's high-grade dysplasia with spray cryotherapy.

BACKGROUND AND AIMS: Recurrent disease after endoscopic ablation of Barrett's esophagus should be detected early to prevent malignant progression. We assessed the incidence and patterns of disease recurrence in patients after liquid nitrogen spray cryotherapy ablation of Barrett's esophagus with high grade dysplasia (HGD), including the area below the neosquamocolumnar junction (NSCJ). PATIENTS AND METHODS: This is a single-center, retrospective study of prospectively collected data on consecutive cases of endoscopic ablation with liquid nitrogen spray cryotherapy for Barrett's HGD. Post-treatment surveillance biopsies were obtained of suspicious lesions and in 4 quadrants every 1 cm in the treated esophagus and just below the NSCJ. Primary outcome measures were location and histology of recurrent disease. RESULTS: 36 patients (median age 62 years, 92% men) were enrolled, and 11 (30%) developed recurrent disease in a median of 6.5 months; three developed a second recurrence. Ten recurrences (71%) were identified below the NSCJ in 9 patients, including HGD (4), low grade dysplasia (LGD) (2), and intestinal metaplasia (4). Six recurrences were identified in the treated esophagus in five patients, including intramucosal cancer (1), HGD (1), and intestinal metaplasia (4). Two patients had recurrent disease involving both locations. Ultimately 33 patients (92%) achieved a complete response. Diagnosis in the remaining three was LGD (1) and intestinal metaplasia (2). CONCLUSION: Most patients with recurrent intestinal metaplasia with or without dysplasia after ablation achieve a complete response. Recurrent disease commonly involves the area just below the NSCJ. Surveillance endoscopies should include this area to accurately identify patients with disease recurrence.

Argon plasma coagulation, bipolar cautery, and cryotherapy: ABC's of ablative techniques.

A variety of endoscopic ablation modalities are available for the treatment of Barrett's esophagus. Multiple studies have evaluated the use of argon plasma coagulation, mostly in nondysplastic Barrett's esophagus. Significant variations in technique, end points, and follow-up exist between studies, but in most cases argon plasma coagulation is associated with unacceptable rates of persistent intestinal metaplasia and recurrence after completion of treatment. In addition, serious adverse events including perforation and stricture formation are reported. Multipolar electrocoagulation has been studied less thoroughly, but in prospective trials significant rates of persistent and recurrent intestinal metaplasia have also been reported. Lasers and heater probes have been tried in small numbers. Endoscopic cryotherapy ablation is a relatively new technique with studies focusing on high-grade dysplasia and early-stage cancer in high-risk patients. It has an acceptable safety profile, and early results show response in a significant number of patients in whom other modalities have failed.

Evaluation of performance of EUS-FNA in preoperative lymph node staging of cancers of esophagus, lung, and pancreas.

We reviewed the cytologic and histologic diagnoses and EUS report of 77 consecutive patients who had undergone EUS-FNA preoperative staging for esophageal, lung, and pancreatic cancers at our institution. A total of 122 EUS-FNA lymph nodes were identified. Thirty of 77 cases had histologic follow-up. Using surgical node staging and/or surgical resection as the reference standard, the sensitivity, specificity, accuracy, and positive and negative predictive values were 75%, 95%, 89%, 86%, and 90%, respectively, for EUS-FNA node staging. We compared cytologically malignant and benign lymph node groups with eight EUS parameters including the total number of lymph nodes found by EUS, the shape, margin, long axis, short axis, echogenicity, location of the lymph node, and EUS tumor staging. We found that the short axis is the best EUS feature to predict malignancy. Lymph nodes found in an abdominal location in esophageal and lung cancer are likely malignant.

Examining lactate in severe TBI using proton magnetic resonance spectroscopy.

PRIMARY OBJECTIVE: Clinical management of acute traumatic brain injury (TBI) has emphasized identification of secondary mechanisms of pathophysiology. An important objective in this study is to use proton magnetic resonance spectroscopy (pMRS) to examine early metabolic disturbance due to TBI. RESEARCH DESIGN: The current design is a case study with repeated measures. METHOD AND PROCEDURE: Proton magnetic resonance imaging was used to examine neurometabolism in this case of very severe brain trauma at 9 and 23 days post-injury. MRI was performed on a clinical 1.5 Tesla scanner. MAIN OUTCOMES AND RESULTS: These data also reveal that pMRS methods can detect lactate elevations in an adult surviving severe head trauma and are sensitive to changes in basic neurometabolism during the first month of recovery. CONCLUSIONS: The current case study demonstrates the sensitivity of pMRS in detecting metabolic alterations during the acute recovery period. The case study reveals that lactate elevations may be apparent for weeks after severe neurotrauma. Further work in this area should endeavour to determine the ideal time periods for pMRS examination in severe TBI as well as the ideal locations of data acquisition (e.g. adjacent or distal to lesion sites).

Enbucrilate for gastric varices: extended experience in 92 patients.

AIM: We assessed N-2-butyl-cyanoacrylate (enbucrilate) in 92 patients with gastric variceal bleeding under an FDA-approved investigation. These results extend our prior report of the first 44 patients. METHOD: Injection was performed with enbucrilate and ethiodol (1:1). Eighty patients had portal hypertension and 12 had splenic vein thrombosis. RESULTS: In the portal hypertensive group, re-bleeding from gastric varices was seen in 4 of 80 (5%) from 0 to 72 h, 5 of 76 (6.5%) from > 72 h to 3 months and 9 of 51 (17%) from > 3 months to 1 year. Re-bleeding and survival were significantly related to the Child-Pugh class. In the splenic vein thrombosis group (n = 12), there was early rebleeding in 2 (17%) patients from 0 to 72 h, 1 (8%) from > 72 h to 3 months and none in the chronic phase (> 3 months to 1 year) although 1-year survival in this group was only 6 (50%) due to the underlying malignancy in most. Serious embolization was suspected in 2 patients (2%). CONCLUSION: Enbucrilate offers an important intervention in gastric variceal bleeding which should be further studied in the US. A randomized trial is warranted to compare this intervention to radiological therapy.

Transcriptional profiling suggests that Barrett's metaplasia is an early intermediate stage in esophageal adenocarcinogenesis.

To investigate the relationship between Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC), we determined gene expression profiles of discrete pathological stages of esophageal neoplasia using a sequence-verified human cDNA microarray. Fifty one RNAs, comprising 24 normal esophagi (NE), 18 BEs, and nine EACs were hybridized to cDNA microarrays. Five statistical analyses were used for the data analysis. Genes showing significantly different expression levels among the three sample groups were identified. Genes were grouped into functional categories based on the Gene Ontology Consortium. Surprisingly, the expression pattern of BE was significantly more similar to EAC than to NE, notwithstanding the known histopathologic differences between BE and EAC. The pattern of NE was clearly distinct from that of EAC. Thirty-six genes were the most differentially modulated, according to these microarray data, in BE-associated neoplastic progression. Twelve genes were significantly differentially expressed in cancer-associated BE's plus EAC (as a single combined tissue group) vs noncancer-associated BE's. These genes represent potential biomarkers to diagnose EAC at its early stages. Our results demonstrate that molecular events at the transcriptional level in BE are remarkably similar to BE's-associated adenocarcinoma of the esophagus. This finding alarmingly implies that BE is biologically closer to cancer than to normal esophagus, and that the cancer risk of BE is perhaps higher than we had imagined. These findings suggest that changes modulated at the molecular biologic level supervene earlier than histologic changes, and that BE is an early intermediate stage in the process of EAC.

Trimodality treatment versus surgery alone for esophageal cancer. A stratified analysis with minimally invasive pretreatment staging.

BACKGROUND: Accurate pretreatment staging of esophageal cancer (EC) is important in the evaluation and comparison of results of different treatment modalities. Few studies using minimally invasive staging techniques for this purpose have been reported. We previously demonstrated the usefulness of the thoracoscopic/laparoscopic (Ts/Ls) technique in pretreatment staging of EC. This study was conducted to evaluate the impact of trimodality based on pretreatment Ts/Ls staging diagnosis on EC. METHODS: A retrospective study was performed on 2 groups of EC patients. Group A (44 patients) underwent pretreatment Ts/Ls staging and had trimodality treatment. Preoperative therapy consisted of concurrent chemotherapy (5-FU + cisplatinum) and radiotherapy. Group B (33 patients) underwent surgery alone. The study focused on stratified comparison of patterns of recurrence and survival in different pretreatment surgical T, N, and TNM stage categories. RESULTS: The 3-year disease free survival of Group A was 40.8% with a median survival of 32.0 months, it was 43.6% with a median survival of 23.6 months in Group B. The difference was not significant (p=0.87). There was no difference in recurrence pattern between the 2 groups. Patients with squamous cell carcinoma in Group A had no local recurrence during the follow-up period while those in Group B had a high local recurrence rate of 40% (p<0.005). When stratified by T factor, patients with locally advanced T stage (T3-4) in Group A had a lower distant recurrence rate than their counterpart patients in Group B (9.1 vs 38.5%, p=0.03), they had a better survival but the difference was not significant (3-year disease free survival: 41.7 vs 17.9%, p=0.14). There were no significant differences in recurrence pattern and survival in different N categories and TNM stages between 2 groups. Multivariate analysis showed that only pretreatment surgical N status was an independent prognostic factor for the whole group (p=0.02). CONCLUSIONS: Pretreatment Ts/Ls staging can provide accurate staging information for EC patients. Trimodality treatment was successful in local control for patients with squamous cell carcinoma. It was effective in reducing distant recurrence and might prolong survival in patients with advanced T stages. Pretreatment lymph node status was the most important prognosticator regardless of treatment modality. Pretreatment pathological staging should be included in the future clinical trials on multimodality treatments in EC patients.

Global gene expression profiling in Barrett's esophagus and esophageal cancer: a comparative analysis using cDNA microarrays.

In order to identify and contrast global gene expression profiles defining the premalignant syndrome, Barrett's esophagus, as well as frank esophageal cancer, we utilized cDNA microarray technology in conjunction with bioinformatics tools. We hybridized microarrays, each containing 8000 cDNA clones, to RNAs extracted from 13 esophageal surgical or endoscopic biopsy specimens (seven Barrett's metaplasias and six esophageal carcinomas). Hierarchical cluster analysis was performed on these results and displayed using a color-coded graphic representation (Treeview). The esophageal samples clustered naturally into two principal groups, each possessing unique global gene expression profiles. After retrieving histologic reports for these tissues, we found that one main cluster contained all seven Barrett's samples, while the remaining principal cluster comprised the six esophageal cancers. The cancers also clustered according to histopathological subtype. Thus, squamous cell carcinomas (SCCAs) constituted one group, adenocarcinomas (ADCAs) clustered separately, and one signet-ring carcinoma was in its own cluster, distinct from the ADCA cluster. We conclude that cDNA microarrays and bioinformatics show promise in the classification of esophageal malignant and premalignant diseases, and that these methods can be applied to small biopsy samples.

Gender-related differences in acute rehabilitation lengths of stay, charges, and functional outcomes for a matched sample with spinal cord injury: a multicenter investigation.

OBJECTIVE: To examine the effects of gender on length of stay (LOS), treatment costs, and outcomes by using a matched sample of patients with spinal cord injury (SCI). DESIGN: A 2 x (15 x 3) mixed, block design was used retrospectively to analyze the impact of gender on subjects matched for age, American Spinal Injury Association (ASIA) motor impairment classification, and level of neurologic injury. SETTING: Twenty medical centers in the federally sponsored Spinal Cord Injury Model Systems project. PARTICIPANTS: One thousand seventy-four adult patients with SCI admitted between 1988 and 1998 were assessed at acute-care admission, inpatient rehabilitation admission, and inpatient rehabilitation discharge. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: ASIA motor index and FIM instrument admission, discharge, and efficiency scores; rehabilitation LOS and medical care charges; and discharge disposition. RESULTS: Analysis revealed no gender-related differences in FIM motor scores on admission and discharge. No differences in FIM motor efficiencies or daily change were observed. No significant differences were found for ASIA motor scores on acute-care admission and rehabilitation discharge. No differences in acute rehabilitation LOS and charges were observed. No gender-related differences were seen in the likelihood of discharge to an institutional setting. CONCLUSION: Gender was not a significant factor in functional outcome of SCI patients after acute rehabilitation.

A controlled study of MRI signal hyperintensities in older depressed patients with and without hypertension.

OBJECTIVES: To compare the frequency/severity of signal hyperintensities--likely markers of cerebrovascular disease--in the subcortical gray and deep white matter on magnetic resonance imaging (MRI) scans of brains of hypertensive and normotensive older depressed and nondepressed comparison subjects. DESIGN: Between-groups comparison of cross-sectional MRI data employing analyses of covariance controlling for the effects of age, gender, and height. SETTING: A comprehensive inpatient-outpatient geriatric psychiatry service in a university hospital. PARTICIPANTS: Nondemented older depressed (n = 81) and nondepressed comparison (n = 70) subjects divided into four groups (hypertensive depressed (n = 40), hypertensive normals (n = 21), normotensive depressed (n = 41), normotensive normals (n = 49)). MEASUREMENTS: Signal hyperintensities were rated on T-2 weighted MRI scans blind to patient diagnoses employing two standardized hyperintensity rating systems (Fazekas, Boyko). RESULTS: Hypertensive depressives had significantly more- severe hyperintensity ratings in both subcortical gray and deep white matter than did normotensive depressives and controls (P < .05) and significantly more-severe hyperintensity ratings only in subcortical gray matter (P < .05) than did hypertensive controls. Hypertensive controls had significantly more-severe ratings in deep white matter than either normotensive group (P < .05). CONCLUSIONS: Findings suggest a relationship between deep white matter hyperintensities and hypertension (regardless of depressive state), and a particular role of subcortical gray matter hyperintensities (possibly interacting with more-severe deep white matter lesions) in older depressed hypertensives, as compared with older depressed normotensives of similar ages and severity of depression. These data support possible heterogeneous pathogenic contributions in late-life depression subgroups, one of which appears to be influenced by cerebrovascular disease.

Pretreatment surgical lymph node staging predicts results of trimodality therapy in esophageal cancer.

OBJECTIVE: Prediction of responders to induction therapy in esophageal cancer (EC) patients is important. In this study, we evaluated the role of thoracoscopic/laparoscopic (Ts/Ls) staging in prediction of treatment response and survival in EC patients with trimodality treatment. METHODS: Retrospective study of EC patients who had undergone Ts/Ls staging and received trimodality treatment at the University of Maryland Medical Center and the Baltimore Veterans Administration Hospitals from July, 1991 to December, 1999. Preoperative therapy consisted of concurrent chemotherapy (5-FU + cisplatinum) and radiotherapy. RESULTS: Forty-four EC patients who underwent pretreatment Ts/Ls staging during the study period were able to complete concurrent chemoradiotherapy followed by surgical resection. There were 36 men and 8 women aged 40 to 77 (median age 62). Twenty-seven (61.4%) patients were found to have lymph node metastasis by surgical staging. Fourteen patients (31.8%) had a pathologic complete response. Patients with positive lymph nodes had a lower response rate than those with negative lymph nodes (14.8% vs. 58.8%, P=0.006). Other clinicopathologic features including gender, weight loss, clinical TNM stage, surgical T stage, and histology did not correlate with treatment response. Univariate analysis showed that weight loss and treatment response were important prognostic factors for disease-free survival (P=0.01 and P=0.02, respectively). Histology, surgical N stage and surgical TNM stage appeared to be associated with prognosis (P=0.067-0.097). Multivariate analysis revealed that only surgical N status and weight loss were significant prognostic factors (P=0.05, and P=0.006, respectively). CONCLUSIONS: Surgical Ts/Ls staging provides accurate evaluation of tumor spread in EC patients. Pretreatment N status was the single most important predictor of response to induction treatment as well as a reliable prognosticator of survival.