Christos T. Nakas

The MoCA Well-suited screen for cognitive impairment in Parkinson disease

Objective: To establish the diagnostic accuracy of the Montreal Cognitive Assessment (MoCA) when screening externally validated cognition in Parkinson disease (PD), by comparison with a PD-focused test (Scales for Outcomes in Parkinson disease–Cognition [SCOPA-COG]) and the standardized Mini-Mental State Examination (S-MMSE) as benchmarks. Methods: A convenience sample of 114 patients with idiopathic PD and 47 healthy controls was examined in a movement disorders center. The 21 patients with dementia (PD-D) were diagnosed using Movement Disorders Society criteria, externally validated by detailed independent functional and neuropsychological tests. The 21 patients with mild cognitive impairment (PD-MCI) scored 1.5 SD or more below normative data in at least 2 measures in 1 of 4 cognitive domains. Other patients had normal cognition (PD-N). Results: Primary outcomes using receiver operating characteristic (ROC) curve analyses showed that all 3 mental status tests produced excellent discrimination of PD-D from patients without dementia (area under the curve [AUC], 87%–91%) and PD-MCI from PD-N patients (AUC, 78%–90%), but the MoCA was generally better suited across both assessments. The optimal MoCA screening cutoffs were <21/30 for PD-D (sensitivity 81%; specificity 95%; negative predictive value [NPV] 92%) and <26/30 for PD-MCI (sensitivity 90%; specificity 75%; NPV 95%). Further support that the MoCA is at least equivalent to the SCOPA-COG, and superior to the S-MMSE, came from the simultaneous classification of the 3 PD patient groups (volumes under a 3-dimensional ROC surface, chance = 17%: MoCA 79%, confidence interval [CI] 70%–89%; SCOPA-COG 74%, CI 62%–86%; MMSE-Sevens item 56%, CI 44%–68%; MMSE-World item 62%, CI 50%–73%). Conclusions: The MoCA is a suitably accurate, brief test when screening all levels of cognition in PD.

Accuracy and cut-off point selection in three-class classification problems using a generalization of the Youden index

We study properties of the index J(3), defined as the accuracy, or the maximum correct classification, for a given three-class classification problem. Specifically, using J(3) one can assess the discrimination between the three distributions and obtain an optimal pair of cut-off points c(1)<c(2) in the sense that the sum of the correct classification proportions will be maximized. It also serves as the generalization of the Youden index in three-class problems. Parametric and non-parametric approaches for estimation and testing are considered and methods are applied to data from an MRS study on human immunodeficiency virus (HIV) patients.

Resveratrol ameliorates hypoxia/ischemia-induced behavioral deficits and brain injury in the neonatal rat brain

Hypoxia-ischemia (HI) induced injury of the neonatal brain accounts for behavioral deficits concerning mainly neurological reflexes, sensorimotor functions and learning/memory disabilities that may evolve throughout development. The positive biological effects of resveratrol, a natural compound with anti-oxidant/anti-inflammatory properties found mainly in red wine have been indicated recently. Aim of this study was to investigate the delayed outcome of early administration of resveratrol in an experimental model of hypoxic-ischemic encephalopathy, by means of behavioral analysis and late neuropathological examination. Seven-day-old (P7) rats were separated into 3 groups: Group 1 underwent HI and treated with resveratrol. Group 2 (HI-treated) was subjected to HI and received same volume of saline. Group 3 (sham-operated) was the control group. A battery of behavioral tests was performed from days P8-P66, during which early reflexes (righting reflex, gait, geotaxis), sensorimotor (rope suspension, beam walking, rotarod) and learning/memory function (passive avoidance, Morris water-maze) were examined. Significant difference among the groups was observed in righting reflex, rotarod and water maze tests in which the resveratrol group almost reached the performance of the control animals. The other behavioral tests showed that control and resveratrol groups were better compared to HI, although not significant. Neuropathology study revealed a remarkable reduction of the infarct and preservation of myelination after resveratrol treatment, which was in most cases correlated with the better performance of the resveratrol group. These findings indicate that long-term neuroprotective effect of resveratrol on neonatal HI-induced gray and white matter damage might be associated with the preservation of behavioral functions.

Construction of confidence regions in the ROC space after the estimation of the optimal Youden index-based cut-off point

After establishing the utility of a continuous diagnostic marker investigators will typically address the question of determining a cut-off point which will be used for diagnostic purposes in clinical decision making. The most commonly used optimality criterion for cut-off point selection in the context of ROC curve analysis is the maximum of the Youden index. The pair of sensitivity and specificity proportions that correspond to the Youden index-based cut-off point characterize the performance of the diagnostic marker. Confidence intervals for sensitivity and specificity are routinely estimated based on the assumption that sensitivity and specificity are independent binomial proportions as they arise from the independent populations of diseased and healthy subjects, respectively. The Youden index-based cut-off point is estimated from the data and as such the resulting sensitivity and specificity proportions are in fact correlated. This correlation needs to be taken into account in order to calculate confidence intervals that result in the anticipated coverage. In this article we study parametric and non-parametric approaches for the construction of confidence intervals for the pair of sensitivity and specificity proportions that correspond to the Youden index-based optimal cut-off point. These approaches result in the anticipated coverage under different scenarios for the distributions of the healthy and diseased subjects. We find that a parametric approach based on a Box-Cox transformation to normality often works well. For biomarkers following more complex distributions a non-parametric procedure using logspline density estimation can be used.

Population‐specific demography and invasion potential in medfly

Biological invasions are constantly gaining recognition as a significant component of global change. The Mediterranean fruit fly (medfly) constitutes an ideal model species for the study of biological invasions due to its (1) almost cosmopolitan geographic distribution, (2) huge economic importance, and (3) well-documented invasion history. Under a common garden experimental set up, we tested the hypothesis that medfly populations obtained from six global regions [Africa (Kenya), Pacific (Hawaii), Central America (Guatemala), South America (Brazil), Extra–Mediterranean (Portugal), and Mediterranean (Greece)] have diverged in important immature life-history traits such as preadult survival and developmental times. We also tested the hypothesis that medfly populations from the above regions exhibit different population growth rates. For this purpose, data on the life history of immatures were combined with adult survival and reproduction data derived from an earlier study in order to calculate population parameters for the above six populations. Our results clearly show that medfly populations worldwide exhibit significant differences in preadult survival, developmental rates of immatures and important population parameters such as the intrinsic rate of increase. Therefore, geographically isolated medfly populations may share different invasion potential, since population growth rates could influence basic population processes that operate mostly during the last two stages of an invasion event, such as establishment and spread. Our findings provide valuable information for designing population suppression measures and managing invasiveness of medfly populations worldwide.

Prolonged pupal dormancy is associated with significant fitness cost for adults of Rhagoletis cerasi (Diptera: Tephritidae)

In temperate areas, dormancy (diapause and/or quiescence) enables herbivorous insect species to persist and thrive by synchronizing growth and reproduction with the seasonal phenology of their host plants. Within-population variability in dormancy increases survival chances under unpredictable environmental changes. However, prolonged dormancy may be costly, incurring trade-offs in important adult fitness traits such as life span and reproduction. We used the European cherry fruit fly, Rhagoletis cerasi, a stenophagous, univoltine species that overwinters in the pupal stage for usually one or more years to test the hypotheses that prolonged dormancy of pupae has trade-offs with body size, survival and reproduction of the resulting adults. We used two geographically isolated populations of R. cerasi to compare the demographic traits of adults obtained from pupae subjected to one or two cycles of warm-cold periods (annual and prolonged dormancy respectively). Regardless of population, adults from pupae that experienced prolonged dormancy were larger than counterparts emerging within 1year. Prolonged dormancy did not affect adult longevity but both lifetime fecundity and oviposition were significantly decreased. Extension of the life cycle of some individuals in R. cerasi populations in association with prolonged dormancy is likely a bet-hedging strategy.

Physiological and biological patterns of a highland and a coastal population of the European cherry fruit fly during diapause

Adult emergence of univoltine temperate insect species and its synchronization with specific host phenological stages is mainly regulated by obligatory pupal diapause. Although a few studies have investigated the factors affecting diapause intensity, little attention has been paid to the physiological alterations and metabolic regulation that take place during diapause. Here, we describe differences in diapause between a highland and a coastal Greek population of the European cherry fruit fly Rhagoletis cerasi, a major pest of sweet and sour cherries in many European countries. Pupae of both populations were exposed to the environmental conditions prevailing in the two areas and diapause termination was observed under laboratory conditions. The regulation of energetic metabolites during the long pupae stage was examined under both field and laboratory conditions. Differences in diapause intensity revealed that the two populations have adapted to the local geographical and climatic conditions and have different requirements for low temperatures to terminate diapause. The coastal population undergoes a shorter diapause and adults emerge more rapidly, especially in the highland area. The highland population failed to terminate diapause (<40% adult emergence) in the coastal area. Both populations draw on their major energetic reserves (lipids and protein) similarly during diapause. Nevertheless, regulation of carbohydrate and glycogen reserves seems to vary between the populations: major peaks of these stored nutrients occur on different dates in the two populations, suggesting a differential regulation. Differences in diapause intensity imply a genetic differentiation between the two populations. The importance of our findings in understanding the physiological patterns during obligatory diapause of a univoltine insect species, as well as the practical implications for the development of specific phenological models for the European cherry fruit fly are discussed.

Assessing multiple-group diagnostic problems with multi-dimensional receiver operating characteristic surfaces: Application to proton MR Spectroscopy (MRS) in HIV-related neurological injury

We present the multi-dimensional Receiver Operating Characteristic (ROC) surface, a plot of the true classification rates of tests based on levels of biological markers, for multi-group discrimination, as an extension of the ROC curve, commonly used in two-group diagnostic testing. The volume under this surface (VUS) is a global accuracy measure of a test to classify subjects in multiple groups and useful to detect trends in marker measurements. We used three-dimensional ROC surfaces, and associated VUS, to discriminate between HIV-negative (NEG), HIV-positive neurologically asymptomatic (NAS) subjects and patients with AIDS demential complex (ADC), using brain metabolites measured by proton MRS. These were ratios of markers of inflammation, Choline (Cho) and myoinositol (MI), and brain injury, N-acetyl aspartate (NAA), divided by Creatine (Cr), measured in the basal ganglia and the frontal white matter. Statistically significant trends were observed in the three groups with respect to MI/Cr (VUS=0.43; 95% confidence interval (CI) 0.33-0.53), Cho/Cr (0.36; 0.27-0.45) in the basal ganglia and NAA/Cr in the frontal white matter (FWM) (0.29; 0.20-0.38), suggesting a continuum of injury during the neurologically asymptomatic stage of HIV infection, particularly with respect to brain inflammation. Adjusting for age increased the combined classification accuracy of age and NAA/Cr (p=0.053). Pairwise comparisons suggested that neuronal damage associated with NAA/Cr decreases was mainly observed in individuals with ADC, raising issues of synergism between HIV infection and age and possible acceleration of neurological deterioration in an aging HIV-positive population. The three-dimensional ROC surface and its associated VUS are useful for assessing marker accuracy, detecting data trends and offering insight in disease processes affecting multiple groups.

Diapause termination of Rhagoletis cerasi pupae is regulated by local adaptation and phenotypic plasticity: escape in time through bet-hedging strategies

Persistence and thriving of univoltine, herbivore insect species of the temperate zone rely on obligate diapause response that ensures winter survival and synchronization with host phenology. We used a stenophagous fruit fly (Rhagoletis cerasi) with obligate pupae diapause to determine genetic and environmental effects on diapause intensity of geographically isolated populations with habitat heterogeneity. Pupae from two Greek and one German populations with various gene flow rates were exposed at five constant chilling temperatures (0–12 °C) for different durations and then incubated at a high temperature until all adults have emerged. Pupae diapause intensity differs among Greek and German populations, suggesting an adaptive response to habitat heterogeneity (mostly differences in phenology patterns of local host cultivars). Moderately warm winter temperatures, such as 8 °C, promote diapause termination in all three populations. Insufficient chilling (short duration or warmer temperatures) regulates the expression of prolonged dormancy. Interestingly, extended chilling (longer than required for terminating diapause) ‘return’ pupae to another (facultative) cycle of dormancy enabling adults to emerge during the next appropriate ‘window of time’; a strategy first time reported for univoltine insects. Consequently, diapause duration of R. cerasi is determined both by i) the adaptive response to local climatic conditions (annual dormancy) and ii) the plastic responses to interannual climatic variability resulting in two types of long life cycles within populations, prolonged and facultative dormancy as response to insufficient chilling and extended exposure to chilling, respectively. Long life cycles are expressed as a part of dormancy bet‐hedging strategies of R. cerasi populations.

Early abnormal amplitude-integrated electroencephalography (aEEG) is associated with adverse short-term outcome in premature infants.

BACKGROUND In preterm infants with IVH the electrocortical background activity is affected and there is a correlation between the severity of cerebral injury to the degree of depression, however the usefulness of the early aEEG recordings has hardly been determined. AIM To identify early aEEG features that could be used as prognostic markers for severe brain injury in prematures. METHODS In 115 infants, 25-32 wk GA, aEEG recordings during the first 72 h of life were correlated with head ultrasound findings. Continuity (Co), sleep-wake cycling (Cy) and amplitude of the lower border (LB) of the aEEG were evaluated by semi-quantitative analysis. RESULTS The infants were divided into four groups based on head ultrasound findings: A (n=72, normal), B [n=16, grades 1-2 intraventricular hemorrhage (IVH)], C (n=21, grades 3-4 IVH) and D (n=6, periventricular leukomalacia). 18 infants (16 of group C and 2 of group D) died during hospitalization. Significantly lower values of all aEEG features were found in group C infants. The presence of pathological tracings (burst-suppression, continuous low-voltage, flat trace) or discontinuous low-voltage (DLV), the absence of Cy and LB<3 μV in the initial aEEG displayed a sensitivity of 88.9%, 63% and 51.9% respectively, for severe brain injury. Logistic regression of aEEG features and GA to the presence or absence of severe injury revealed that only Co was significantly correlated to outcome. Using this feature 83.19% of cases were correctly classified. CONCLUSION Pathological tracings or DLV in the initial aEEG is predictive for poor short-term outcome in premature neonates.