Bedda L. Rosario

Basal Cerebral Metabolism May Modulate the Cognitive Effects of Aβ in Mild Cognitive Impairment: An Example of Brain Reserve

Inverse correlations between amyloid-β (Aβ) load measured by Pittsburgh Compound-B (PiB) positron emission tomography (PET) and cerebral metabolism using [18F]fluoro-2-deoxy-d-glucose (FDG) in Alzheimers disease (AD) patients, suggest local Aβ-induced metabolic insults. However, this relationship has not been well studied in mild cognitive impairment (MCI) or amyloid-positive controls. Here, we explored associations of Aβ deposition with metabolism via both region-of-interest-based and voxel-based analyses in amyloid-positive control subjects and patients with MCI or AD. Metabolism in parietal and precuneus cortices of AD patients was negatively correlated with PiB retention locally, and more distantly with PiB retention in frontal cortex. In amyloid-positive controls, no clear patterns in correlations were observed. In MCI patients, there were essentially no significant, negative correlations, but there were frequent significant positive correlations between metabolism and PiB retention. Metabolism in anterior cingulate showed positive correlations with PiB in most brain areas in MCI, and metabolism and PiB retention were positively correlated locally in precuneus/parietal cortex. However, there was no significant increase in metabolism in MCI compared to age-matched controls, negating the possibility that Aβ deposition directly caused reactive hypermetabolism. This suggests that, in MCI, higher basal metabolism could either be exacerbating Aβ deposition or increasing the level of Aβ necessary for cognitive impairment sufficient for the clinical diagnosis of AD. Only after extensive Aβ deposition has been present for longer periods of time does Aβ become the driving force for decreased metabolism in clinical AD and, only in more vulnerable brain regions such as parietal and precuneus cortices.

Consideration of Optimal Time Window for Pittsburgh Compound B PET Summed Uptake Measurements

The standardized uptake value ratio (SUVR, or summed tissue ratio) has been used effectively in Pittsburgh compound B (PiB) PET studies to distinguish subjects who have significant amyloid-β deposition in their brain from those who do not. Relative to quantitative measurements, advantages of the SUVR are improved study feasibility and low test–retest variation; disadvantages include inherent bias (PiB retention overestimation) and potential for time-varying outcomes. The PiB SUVR has proven to be highly correlated with quantitative outcomes and to allow reliable detection of significant group differences (or effective contrasts). In this work, regional PiB SUVRs were examined across 9 time windows to select the window that provided the best trade-offs between bias, correlation, and effective contrast. Methods: A total of 40 dynamic PiB PET studies were performed on controls (n = 16), patients with Alzheimer disease (AD; n = 11), and patients with mild cognitive impairment (MCI; n = 13) (555 MBq [15 mCi], 90-min scan, and arterial blood sampling). The SUVR was computed for five 20-min and four 30-min windows that spanned the 30- to 90-min postinjection period. The SUVRs were compared with Logan graphical distribution volume ratio (DVR) measurements (35–90 min), determined with arterial blood as input and without arterial blood as input (cerebellum as reference). Results: Greater correlation and more bias were generally observed for the SUVR measurement at later times than at earlier times (relative to DVR). The effective contrast between the control and AD PiB SUVRs was slightly better for earlier data than for later data. The temporal dynamics of the SUVR measurement indicated greater stability in the measurement at 40 min after injection. Conclusion: The 50- to 70-min time window provided a good compromise between physiologic validity, stability, sensitivity, and clinical feasibility across the control, MCI, and AD subject data examined in this study. The 40- to 60-min period demonstrated many advantages and should be used in studies limited by low injected dose. Although more biased than the 40- to 60-min SUVR, the 50- to 70-min SUVR was thought to be optimal because of greater measurement stability, which may prove to be important for longitudinal multisite studies performed in control, MCI, and AD subjects that are not dose-limited.

In vivo assessment of amyloid-β deposition in nondemented very elderly subjects

This study examined amyloid‐β (Aβ) deposition in 190 nondemented subjects aged ≥82 years to determine the proportion of Aβ‐positive scans and associations with cognition, apolipoprotein E (APOE) status, brain volume, and Ginkgo biloba (Gb) treatment.

Neuropathy and Poorly Controlled Diabetes Increase the Rate of Surgical Site Infection After Foot and Ankle Surgery

BACKGROUND This prospective study was designed to evaluate the frequency of surgical site infection in patients treated with foot and ankle surgery. Our hypothesis was that patients with complications of diabetes are at increased risk for surgical site infection compared with patients without diabetes and patients with diabetes who do not have diabetic complications. Another goal was to compare the association of neuropathy with surgical site infection in both nondiabetic and diabetic patients. METHODS Two thousand and sixty consecutive surgical cases were evaluated. Group 1 included nondiabetic patients without neuropathy, Group 2 included nondiabetic patients with neuropathy, Group 3 included patients with diabetes but no diabetic complications, and Group 4 included patients with diabetes who had at least one complication of diabetes. RESULTS The surgical site infection rate in this study was 3.1%. Patients with complicated diabetes had a 7.25-fold increased risk of surgical site infection compared with nondiabetic patients without neuropathy and a 3.72-fold increased risk compared with patients with uncomplicated diabetes. Patients with complicated diabetes had a nonsignificant 1.54-fold higher rate of surgical site infection compared with nondiabetic patients with neuropathy. Nondiabetic patients with neuropathy had a significant 4.72-fold increased risk of surgical site infection compared with nondiabetic patients without neuropathy. Despite this, nondiabetic patients with neuropathy did not have a significantly higher rate of surgical site infection than patients with uncomplicated diabetes, and the frequency of surgical site infection in the group with uncomplicated diabetes was not significantly different from that in the nondiabetic patients without neuropathy. Multivariable logistic regression analysis demonstrated that peripheral neuropathy and a hemoglobin A1c of ≥8% were independently associated with surgical site infection. CONCLUSIONS Complicated diabetes increases the risk of surgical site infection after foot and ankle surgery. Patients who had diabetes without complications did not have a greater risk of surgical site infection compared with nondiabetic patients without neuropathy. The presence of neuropathy increases the risk of surgical site infection even in patients without diabetes. Poor long-term glycemic control is also associated with an increased risk of surgical site infection. LEVEL OF EVIDENCE Prognostic Level I. See Instructions for Authors for a complete description of levels of evidence.

Inter-rater reliability of manual and automated region-of-interest delineation for PiB PET

A major challenge in positron emission tomography (PET) amyloid imaging studies of Alzheimers disease (AD) is the reliable detection of early amyloid deposition in human brain. Manual region-of-interest (ROI) delineation on structural magnetic resonance (MR) images is generally the reference standard for the extraction of count-rate data from PET images, as compared to automated MR-template(s) methods that utilize spatial normalization and a single set of ROIs. The goal of this work was to assess the inter-rater reliability of manual ROI delineation for PiB PET amyloid retention measures and the impact of CSF dilution correction (CSF) on this reliability for data acquired in elderly control (n=5) and AD (n=5) subjects. The intraclass correlation coefficient (ICC) was used to measure reliability. As a secondary goal, ICC scores were also computed for PiB outcome measures obtained by an automated MR-template ROI method and one manual rater; to assess the level of reliability that could be achieved using different processing methods. Fourteen ROIs were evaluated that included anterior cingulate (ACG), precuneus (PRC) and cerebellum (CER). The PiB outcome measures were the volume of distribution (V(T)), summed tissue uptake (SUV), and corresponding ratios that were computed using CER as reference (DVR and SUVR). Substantial reliability (ICC≥0.932) was obtained across 3 manual raters for V(T) and SUV measures when CSF correction was applied across all outcomes and regions and was similar in the absence of CSF correction. The secondary analysis revealed substantial reliability in primary cortical areas between the automated and manual SUV [ICC≥0.979 (ACG/PRC)] and SUVR [ICC≥0.977/0.952 (ACG/PRC)] outcomes. The current study indicates the following rank order among the various reliability results in primary cortical areas and cerebellum (high to low): 1) V(T) or SUV manual delineation, with or without CSF correction; 2) DVR or SUVR manual delineation, with or without CSF correction; 3) SUV automated delineation, with CSF correction; and 4) SUVR automated delineation, with or without CSF correction. The high inter-rater reliability of PiB outcome measures in primary cortical areas (ACG/PRC) is important as reliable methodology is needed for the detection of low levels of amyloid deposition on a cross-sectional basis and small changes in amyloid deposition on a longitudinal basis.

Fibrosis Reduces Severity of Acute-on-Chronic Pancreatitis in Humans

BACKGROUND & AIMS Acute pancreatitis (AP) and chronic pancreatitis (CP) share etiologies, but AP can be more severe and is associated with a higher rate of mortality. We investigated features of CP that protect against severe disease. The amount of intrapancreatic fat (IPF) is increased in obese patients and fibrosis is increased in patients with CP, so we studied whether fibrosis or fat regulate severity of AP attacks in patients with CP. METHODS We reviewed records from the University of Pittsburgh Medical Center/Presbyterian Hospital Autopsy Database (1998-2008) for patients with a diagnosis of AP (n = 23), CP (n = 35), or both (AP-on-CP; n = 15). Pancreatic histology samples from these patients and 50 randomly selected controls (no pancreatic disease) were analyzed, and IPF data were correlated with computed tomography data. An adipocyte and acinar cell Transwell coculture system, with or without collagen type I, was used to study the effects of fibrosis on acinar-adipocyte interactions. We studied the effects of nonesterified fatty acids (NEFAs) and adipokines on acinar cells in culture. RESULTS Levels of IPF were significantly higher in nonobese patients with CP than in nonobese controls. In patients with CP or AP-on-CP, areas of IPF were surrounded by significantly more fibrosis than in controls or patients with AP. Fat necrosis-associated peri-fat acinar necrosis (PFAN, indicated by NEFA spillage) contributed to most of the necrosis observed in samples from patients with AP; however, findings of peri-fat acinar necrosis and total necrosis were significantly lower in samples from patients with CP or AP-on-CP. Fibrosis appeared to wall off the fat necrosis and limit peri-fat acinar necrosis, reducing acinar necrosis. In vitro, collagen I limited the lipolytic flux between acinar cells and adipocytes and prevented increases in adipokines in the acinar compartment. This was associated with reduced acinar cell necrosis. However, NEFAs, but not adipokines, caused acinar cell necrosis. CONCLUSIONS Based on analysis of pancreatic samples from patients with CP, AP, or AP-on-CP and in vitro studies, fibrosis reduces the severity of acute exacerbations of CP by reducing lipolytic flux between adipocytes and acinar cells.

The Association Between Perioperative Allogeneic Transfusion Volume and Postoperative Infection in Patients Following Lumbar Spine Surgery

BACKGROUND Perioperative allogeneic red blood cell transfusion is a risk factor for surgical site infection. The purpose of this study was to determine if the volume of perioperative allogeneic red blood cell transfusion influences the risk of surgical site infection following lumbar spine procedures. METHODS A retrospective matched case control study was performed by reviewing all patients who had undergone lumbar spine surgery at our institution from 2005 to 2009. Surgical site infections (spinal or iliac crest) were identified, all within thirty days of the procedure. Controls were matched to the infection cohort according to age, sex, body mass index, diabetic status, smoking status, Charlson Comorbidity Index, length of surgery, and procedure. A conditional logistic regression was performed to examine the association between transfusion volume and surgical site infection. The results were summarized by an odds ratio. RESULTS A total of 1799 lumbar procedures were identified with an infection rate of 3.1% (fifty-six cases). On the basis of the numbers, there was no significant difference in the matched variables between the infection cohort and the matched controls. The volume of transfusion was significantly associated with surgical site infection (odds ratio, 4.00 [95% confidence interval, 1.96 to 8.15]) after adjusting for both unmatched variables of preoperative hemoglobin level and volume of intraoperative blood loss. CONCLUSIONS In this retrospective matched case control study, the association between surgical site infection following lumbar spine surgery and volume of perioperative allogeneic red blood cell transfusion was supported.

A Longitudinal Study of Insomnia and Other Sleep Complaints in Adolescents with and without Alcohol Use Disorders

BACKGROUND Sleep disturbances are both common and well-characterized in adults with alcohol use disorders (AUDs), but have received little study in adolescents with AUDs. Furthermore, a handful of studies suggest that sleep complaints are a risk factor for AUDs. However, no published studies have yet examined the longitudinal course of sleep complaints in adolescents with AUDs; in particular, it remains unclear how persistent AUD-associated sleep complaints are in this age group, and what types of sleep complaints are most relevant to alcohol-use symptoms. We investigated these questions in a 5-year longitudinal study of adolescents with and without AUDs at baseline. METHODS Participants were 696 adolescents (age 12 to 19) from a longitudinal study at the Pittsburgh Adolescent Alcohol Research Center. At baseline, 347 participants had a current AUD (AUD+), while 349 had no current or past AUD (AUD-). We examined sleep and alcohol involvement at baseline as well as 1-, 3-, and 5-year follow-up visits. Sleep variables included self-reported insomnia and hypersomnia, as well as variability in weekday-weekend sleep duration, all at baseline. Covariates included sex, age, current alcohol symptoms, and depression severity. RESULTS The AUD+ group reported more overall sleep disturbance at baseline, including greater insomnia and hypersomnia complaints, and greater variability in weekday-weekend sleep duration. Group differences in insomnia and hypersomnia complaints persisted to the 5- and 3-year follow-ups, respectively. In the AUD- group, greater insomnia complaints at baseline predicted an increase in alcohol symptoms at the 1-year follow-up, while greater variability in sleep duration at baseline predicted an increase in alcohol symptoms at the 3- and 5-year follow-ups. CONCLUSIONS These results complement previous findings in other samples, indicating that insomnia and other sleep problems are a chronic predicament for adolescents with AUDs. The findings also suggest that sleep disturbances may place adolescents without AUDs at an elevated risk of developing alcohol problems.

Magnetic Resonance Imaging Investigation of Macrophages in Acute Cardiac Allograft Rejection After Heart Transplantation

Background—Current immunosuppressive therapy after heart transplantation either generally suppresses the recipient’s entire immune system or is mainly targeting T-lymphocytes. Monocytes/macrophages are recognized as a hallmark of acute allograft rejection, but the roles that they play are not well characterized in vivo, because the tools for accessing in situ macrophage infiltration are lacking. In this study, we used MRI to investigate the role of macrophages in acute heart allograft rejection by cellular and functional MRI with selectively depleted systemic macrophages without affecting other leukocyte population, as well as to explore the possibility that macrophages could be an alternative therapeutic target. Methods and Results—A rodent heterotopic working heart–lung transplantation model was used for studying acute allograft rejection. Systemic macrophages were selectively depleted by treating recipient animals with clodronate-liposomes. Macrophage infiltration in the graft hearts was monitored by cellular MRI with in vivo ultrasmall superparamagnetic iron oxide particles labeling. Graft heart function was evaluated by tagging MRI followed by strain analysis. Clodronate-liposome treatment depletes circulating monocytes/macrophages in transplant recipients, and both cellular MRI and pathological examinations indicate a significant reduction in macrophage accumulation in the rejecting allograft hearts. In clodronate-liposome–treated group, allograft hearts exhibited preserved tissue integrity, partially reversed functional deterioration, and prolonged graft survival, compared with untreated controls. Conclusions—Cardiac cellular and functional MRI is a powerful tool to explore the roles of targeted immune cells in vivo. Our results indicate that macrophages are essential in acute cardiac allograft rejection, and selective depletion of macrophages with clodronate-liposomes protects hearts against allograft rejection, suggesting a potential therapeutic avenue. Our findings show that there is a finite risk of forming an intraventricular mass, presumably from the cellular debris or lipid material. Further optimization of the dosing protocol is necessary before clinical applications.

Radiographic analysis of diabetic midfoot charcot neuroarthropathy with and without midfoot ulceration.

Background: The aim of this study was to evaluate weight-bearing radiographs in patients with and without foot ulcers diagnosed with midfoot Charcot neuroarthropathy (CN) secondary to diabetes mellitus. Methods: One hundred fourteen patients with midfoot CN (50 with foot ulcers and 64 without ulcers) were identified and included in this study. Nine radiographic measurements were made (7 in the sagittal plane and 2 in the transverse plane). Results: CN patients with foot ulcers had significantly greater deformity when assessing the lateral-talar first metatarsal angle, calcaneal pitch, cuboid height, medial column height, calcaneal-fifth metatarsal angle, talar declination, and lateral tibiotalar angle. Two measurements in the transverse plane (hindfoot-forefoot angle and AP talar first metatarsal angle) were not significantly different between the 2 groups. Of patients with foot ulcers, 24% had a lateral talar first metatarsal angle of less than −27 degrees and 80% had a negative cuboid height. Conclusion: Sagittal plane deformities were more likely to be associated with foot ulceration in patients with CN than transverse plane deformities. Lateral column involvement was associated with a worse prognosis than medial column involvement, thus we believe progressive deformity of the lateral column should be monitored closely to prevent foot ulceration. Lateral column involvement could be identified by a decrease in the cuboid height, decreased calcaneal pitch, and decreased lateral calcaneal fifth metatarsal angle. This study can assist physicians in stratifying the risk for both ulceration and need for surgery in patients with CN based on reproducible radiographic measurements. Level of Evidence: Level III, comparative series.