Decreased body mass index in the preclinical stage of autosomal dominant Alzheimer's disease.

The relationship between body-mass index (BMI) and Alzheimer´s disease (AD) has been extensively investigated. However, BMI alterations in preclinical individuals with autosomal dominant AD (ADAD) have not yet been investigated. We analyzed cross-sectional data from 230 asymptomatic members of families with ADAD participating in the Dominantly Inherited Alzheimer Network (DIAN) study including 120 preclinical mutation carriers (MCs) and 110 asymptomatic non-carriers (NCs). Differences in BMI and their relation with cerebral amyloid load and episodic memory as a function of estimated years to symptom onset (EYO) were analyzed. Preclinical MCs showed significantly lower BMIs compared to NCs, starting 11.2 years before expected symptom onset. However, the BMI curves begun to diverge already at 17.8 years before expected symptom onset. Lower BMI in preclinical MCs was significantly associated with less years before estimated symptom onset, higher global Aß brain burden, and with lower delayed total recall scores in the logical memory test. The study provides cross-sectional evidence that weight loss starts one to two decades before expected symptom onset of ADAD. Our findings point toward a link between the pathophysiology of ADAD and disturbance of weight control mechanisms. Longitudinal follow-up studies are warranted to investigate BMI changes over time.

Normal Values for the Full Visual Field, Corrected for Age- and Reaction Time, Using Semiautomated Kinetic Testing on the Octopus 900 Perimeter.

PURPOSE: To determine normal values of the visual field (VF), corrected for age and reaction time (RT) for semiautomated kinetic perimetry (SKP) on the Octopus 900 perimeter, create a model describing the age-dependency of these values, and assess test-retest reliability for each isopter. METHODS: Eighty-six eyes of 86 ophthalmologically healthy subjects (age 11-79 years, 34 males, 52 females) underwent full-field kinetic perimetry with the Octopus 900 instrument. Stimulus size, luminance, velocity, meridional angle, subject age, and their interactions, were used to create a smooth multiple regression mathematical model (V/4e, III/4e, I/4e, I/3e, I/2e, I/1e, and I/1a isopters). Fourteen subjects (2 from each of 7 age groups) were evaluated on three separate sessions to assess test-retest reliability of the isopters. Reaction time (RT) was tested by presenting 12 designated RT-vectors between 10° and 20° within the seeing areas for the III/4e isopter (stimulus velocity, 3°/second). Four RT- vectors were presented at the nasal (0° or 180°), superotemporal (45°), and inferior (270°) meridians. RESULTS: The model fit was excellent (r2 = 0.94). The test-retest variability was less than 5°, and the median decrease in this deviation attributed to aging, per decade, for all age groups and for all stimulus sizes was 0.8°. No significant learning effect was observed for any age group or isopter. CONCLUSION: Age-corrected and RT-corrected normative threshold values for full-field kinetic perimetry can be adequately described by a smooth multiple linear regression mathematical model. TRANSLATIONAL RELEVANCE: A description of the entire kinetic VF is useful for assessing a full characterization of VF sensitivity, determining function losses associated with ocular and neurologic diseases, and for providing a more comprehensive analysis of structure-function relationships.

VFMA: Topographic Analysis of Sensitivity Data From Full-Field Static Perimetry.

PURPOSE: To analyze static visual field sensitivity with topographic models of the hill of vision (HOV), and to characterize several visual function indices derived from the HOV volume. METHODS: A software application, Visual Field Modeling and Analysis (VFMA), was developed for static perimetry data visualization and analysis. Three-dimensional HOV models were generated for 16 healthy subjects and 82 retinitis pigmentosa patients. Volumetric visual function indices, which are measures of quantity and comparable regardless of perimeter test pattern, were investigated. Cross-validation, reliability, and cross-sectional analyses were performed to assess this methodology and compare the volumetric indices to conventional mean sensitivity and mean deviation. Floor effects were evaluated by computer simulation. RESULTS: Cross-validation yielded an overall R2 of 0.68 and index of agreement of 0.89, which were consistent among subject groups, indicating good accuracy. Volumetric and conventional indices were comparable in terms of test-retest variability and discriminability among subject groups. Simulated floor effects did not negatively impact the repeatability of any index, but large floor changes altered the discriminability for regional volumetric indices. CONCLUSIONS: VFMA is an effective tool for clinical and research analyses of static perimetry data. Topographic models of the HOV aid the visualization of field defects, and topographically derived indices quantify the magnitude and extent of visual field sensitivity. TRANSLATIONAL RELEVANCE: VFMA assists with the interpretation of visual field data from any perimetric device and any test location pattern. Topographic models and volumetric indices are suitable for diagnosis, monitoring of field loss, patient counseling, and endpoints in therapeutic trials.

Assessment of functional and morphometric endpoints in patients with non-arteritic anterior ischemic optic neuropathy (NAION).

BACKGROUND: The primary objective of this bi-center explorative pilot study was the quantitative assessment of visual field defects and retinal nerve fiber layer thickness (RNFT) over 6 months in patients with acute non-arteritic anterior ischemic optic neuropathy (NAION), in order to elucidate the natural course of NAION and provide a reference dataset for future treatment studies. METHODS: 16 patients (age 41-80 years, nine males, seven females) suffering from acute NAION and presenting within 7 days after onset of symptoms were included in this study. The following examinations were carried out at the initial visit (month 0) and at months 2, 4 and 6: entire (90°) visual field examination with automated static white-on-white perimetry, quantified by mean defect (MD); peripapillary retinal nerve fiber layer thickness (RNFT) measurement with spectral domain optical coherence tomography (SD-OCT); assessment of distant best correct visual acuity (D-BCVA) and a quantification of the relative afferent pupillary defect (RAPD) using the swinging flashlight test with neutral density filters. Perimetric Mean Defect (MD) and RNFT values were each compared between the consecutive visits using the non-parametric Friedman test. RESULTS: The initial MD was 6.2 dB (IQR 5.0-7.4) without significant changes further on. RNFT was 183 µm (IQR 148-252) initially, decreased significantly at month 2 (78 µm (IQR 71-93) and further at month 4 (64 µm (IQR 58-74) and 6 (61 µm (IQR 52-81), Friedman test, p < 0.001). Initially, RNFT was above normal limits (due to swelling) in 15/16 patients; at month 2 it was below normal limits in 13/16 patients, at month 4 in 12/13 patients and at month 6 in 9/10 patients. 7/16 patients exhibited segmental swelling of the optic disc, whereas the entire circumference of the optic disc showed RNFL thickening in 9/16 patients. CONCLUSION: Functional deficits were present directly after onset of NAION and did not change relevantly further on. Morphological changes comprise severe swelling after onset of NAION, which rapidly turns into atrophy. Already after 2 months more than 80 % of the patients showed a RNFT below normal limits. Progressive RNFL thinning between month 2 and month 4 suggests ongoing atrophy, whereas a stable morphologic end point is reached after month 4.

Decreased retinal sensitivity and loss of retinal nerve fibers in multiple system atrophy.

BACKGROUND AND AIM: In a previous study, retinal nerve fiber layer thickness (RNFLT) loss was shown as part of the neurodegenerative process in multiple system atrophy (MSA). Here, we investigate in a larger cohort of MSA patients whether the RNFLT loss translates into respective visual field defects. METHODS: Spectral domain optical coherence tomography was performed in 20 MSA patients (parkinsonian subtype = 12, cerebellar subtype = 8) to quantify peripapillary RNFLT. Visual field (90°) was analyzed by automated static perimetry to investigate retinal structure/function relationship. Eight data sets did not meet stringent quality criteria, and only 12 data sets were further analyzed. RESULTS: Compared to healthy controls, MSA patients demonstrated a significant reduction of RNFLT in the nasal sectors (p ( nasal-superior ) = 0.02, p ( nasal ) = 0.03, p ( nasal-inferior ) < 0.01), while changes in temporal RNFLT measures (p ( temporal-superior ) = 0.42, p ( temporal ) = 0.34, p ( temporal-inferior ) = 0.25) were not statistically significant compared to healthy controls (ANOVA). MSA patients featured a significant global mean deviation (2.74 dB; p < 0.01) without predominant peripheral visual field defects. Statistical analysis of mean defect in the central (0-30°), peripheral (30-90°) or global (0-90°) visual field revealed no significant correlation (r (2) (central) = 0.11, r (2) (peripheral) = 0.04, r (2) (global) = 0.07) with nasal RNFLT in MSA patients. CONCLUSION: MSA patients feature significant reduction in nasal RNFLT and global mean deviation when compared to healthy controls, consistent with the multi-systemic nature of this neurodegenerative disorder. This finding provides first evidence for two independent deteriorations of the visual system in MSA.

Immune profiling in blood identifies sTNF-R1 performing comparably well as biomarker panels for classification of Alzheimer's disease patients.

BACKGROUND: Alzheimer's disease (AD) has been linked to a state of cerebral and systemic inflammation. The objective of the present study was to determine whether singular markers or a set of inflammatory biomarkers in peripheral blood allow discrimination between AD patients and healthy controls at the individual level. METHODS: Using bead based multiplexed sandwich immunoassays, 25 inflammatory biomarkers were measured in 164 serum samples from individuals with early AD and age-matched cognitively healthy elderly controls. The data set was randomly split into a training set for feature selection and classification training and a test set for class prediction of blinded samples (1 : 1 ratio) to evaluate the chosen predictors and parameters. Multivariate data analysis was performed with use of a support vector machine (SVM). RESULTS: After selection of sTNF-R1 as most discriminative parameter in the training set, the application of SVM to the independent test dataset resulted in a 90.0% correct classification for individual AD and control subjects. CONCLUSIONS: We identified sTNF-R1 from a marker set consisting of 25 inflammatory biomarkers, which allowed SVM-based discrimination of AD patients from healthy controls on a single-subject classification level comparably well as biomarker panels with a clinically relevant accuracy and validity. Although larger sample populations will be needed to confirm this diagnostic accuracy, our study suggests that sTNF-R1 in serum-either as singular marker or incorporated into a biomarker panel-could be a powerful new biomarker for detection of AD. In addition, selective inhibition of TNF-R1 function may represent a new therapeutic approach in AD.

Associating the magnitude of relative afferent pupillary defect (RAPD) with visual field indices in glaucoma patients.

PURPOSE: To identify the variable with the strongest association between the magnitude of the relative afferent pupillary defect (RAPD) and visual field indices in patients with glaucomatous optic neuropathy. METHODS: Seventy-nine consecutive subjects with manifest glaucomatous optic neuropathy at least in one eye were enrolled in this retrospective study. RAPD was assessed with the swinging flashlight test and quantified with a neutral density filter. Perimetry was performed using the fast thresholding strategy German Adaptive Threshold Estimation. The values of the central differential luminance sensitivity (DLS), of the MD (mean defect) and of the 'loss volume' (LVOL) based on the individually modelled 3D hill of vision-the latter two within the eccentricities of 10°, 20° and 30°, respectively-were entered into a linear regression model without intercept as a function of RAPD. RESULTS: An absolute value of RAPD of 0.3 log(10) units or more was present in 20 out of 79 glaucoma subjects (25%). The magnitude of RAPD was most closely associated with LVOL-30° (R(2)=0.77), followed by MD-30° (R(2)=0.73), MD-20° (R(2)=0.71), LVOL-20° (R(2)=0.67), MD-10° (R(2)=0.58), LVOL-10° (R(2)=0.54) and central DLS (R(2)=0.04). CONCLUSIONS: The prevalence of RAPD in glaucoma patients is comparatively small (25%). The magnitude of RAPD in glaucoma subjects is associated most closely with the LVOL within 30° eccentricity (which is the maximum visual field region tested in this study) and most loosely with central DLS, underscoring the impact of the entire (30°) visual field area on the afferent pupillary system.

Optical coherence tomography shows progressive local nerve fiber loss after disc hemorrhages in glaucoma patients.

BACKGROUND AND AIM: The aim of this work is to investigate whether optic disc hemorrhages (ODH) lead to significant loss of nerve fibers at the lesion site over time and whether such a loss is reflected by visual field defects corresponding to the affected nerve fiber bundle. METHODS: In this retrospective study of ten sequential glaucoma patients (ten eyes) with ODH, we used high-resolution OCT circular scans (Spectralis HRA + OCT, Heidelberg Engineering, Heidelberg, Germany) to determine peripapillary retinal nerve fiber layer (RNFL) thickness at the time of ODH presentation and at follow-up visit between 3 and 6 months. Corresponding perimetric data were analyzed for global (mean defect, MD) and localized progression of visual field defects. RESULTS: ODH were mostly located in the inferior quadrant as determined clinically and from fundus photographs. Iterative OCT imaging revealed a significant RNFL reduction in the affected quadrant relative to the respective quadrant in the fellow eye (RNFL change = -2.25 ± 2.69 µm vs. 0.75 ± 2.78 µm, p = 0.01) within 120 ± 43 days. However, only three cases presented with new/progressive nerve fiber bundle defects corresponding to the lesion site within the given follow-up period. CONCLUSIONS: ODH lead to a significantly higher RNFL loss at the lesion site relative to the overall structural progression in glaucoma patients. However, this focal change is not generally reflected by respective nerve fiber bundle defects in the time frame investigated.

Identification of a blood-based biomarker panel for classification of Alzheimer's disease.

An ideal diagnostic test for Alzheimer's disease (AD) should be non-invasive and easily applicable. Thus, there is a clear need to search for biomarkers in blood. In the present study, we have used multivariate data analysis [support vector machine (SVM)] to investigate whether a blood-based biomarker panel allows discrimination between AD patients and healthy controls at the individual level. We collected a total of 155 serum samples from individuals with early AD and age-matched healthy controls and measured serum levels of 24 markers involved in several biological pathways by ELISA. The dataset was randomly split into a training set for predictor discovery and classification training and a test set for class prediction of blinded samples (3:1 ratio) to evaluate the chosen predictors and parameters. After selection of a feature group of the three most discriminative parameters (cortisol, von Willebrand factor, oxidized LDL antibodies) in the training set, the application of SVM to the training/independent test dataset resulted in an 81.7%/87.1% correct classification for AD and control subjects. In conclusion, we identified a panel of three blood markers, which allowed SVM-based distinguishing of AD patients from healthy controls on a single-subject classification level with clinically relevant accuracy and validity. Blood-based biomarkers might have utility in AD diagnostics as screening tool before further classification with CSF biomarkers and imaging. Future studies should examine whether blood-based biomarkers may also be useful to differentiate AD patients from other dementias.

Imaging and Perimetry Society standards and guidelines.

PURPOSE: To provide readers with standards, recommendations, guidelines, and requirements for the application of perimetry to clinical ophthalmic practice and scientific study. METHODS: A working group of perimetry and visual field specialists from many parts of the world constructed a document that would allow current and future perimeters to be assessed by the same criteria. Because hardware and software technology, statistical procedures and clinical conditions are constantly changing, the characteristics in this paper emphasize general concepts rather than specific implementations employed by current devices. RESULTS: Critical aspects of perimetry included indications for perimetry, perimetric techniques, stimulus characteristics, test administration, patient preparation, data display, statistical analysis, interpretation of visual field findings, a glossary of terms and definitions, and standards for comparison of different perimetric tests. Each of these topics is discussed, along with their advantages and disadvantages. CONCLUSIONS: These guidelines serve as a basis for practitioners to evaluate their perimetric needs in relation to their clinical practice and patient population so that informed decisions can be made for visual field testing. In addition, these issues should be used as a cornerstone for future technological and practical improvements to the visual field diagnostic procedures.

Mayday--a microarray data analysis workbench.

UNLABELLED: Mayday is a workbench for visualization, analysis and storage of microarray data. It features a graphical user interface and supports the development and integration of existing and new analysis methods. Besides the infrastructural core functionality, Mayday offers a variety of plug-ins, such as various interactive viewers, a connection to the R statistical environment, a connection to SQL-based databases and different data mining methods, including WEKA-library based methods for classification and various clustering methods. In addition, so-called meta information objects are provided for annotation of the microarray data allowing integration of data from different sources, which is a feature that, for instance, is employed in the enhanced heatmap visualization. SUPPLEMENTARY INFORMATION: The software and more detailed information including screenshots and a user guide as well as test data can be found on the Mayday home page http://www.zbit.uni-tuebingen.de/pas/mayday. The core is published under the GPL (GNU Public License) and the associated plug-ins under the LGPL (Lesser GNU Public License).

cDNA microarray analysis reveals novel candidate genes expressed in human peripheral blood following exhaustive exercise.

It is generally accepted that exhausting endurance exercise exhibits strong effects on the immune system. Such effects have been attributed to changes in the cellular composition of peripheral blood as well as to changes in the expression of plausible candidate genes. The list of candidate genes is far from being complete, since this issue has not yet been investigated in a systematic way. In this study, we used a custom-made cDNA microarray focused on inflammation as a screening approach to study gene expression in eight one-half marathon runners before, immediately after, and 24 h after exercise. Significant differential gene expression was verified by quantitative real-time PCR. Linear regression analysis showed that microarray expression analysis of cell type-specific surface molecules reflects the observed individual cellular shifts in peripheral blood cells with high statistical significance. In line with the results of former studies, we observed an upregulation of mitogen-activated protein kinase-activated protein kinase-2 (MAPKAP-K2), L-selectin, and IL-1 receptor antagonist (IL-1ra) after exhaustive exercise. The main results of this study report, for the first time, the downregulation of CD81; the upregulation of thioredoxin, which may play an important part in anti-oxidative defense; and, surprisingly, the downregulation of the anti-carcinogenic gene glutathione-S-transferase-3 (GSTM3) in peripheral blood. The study shows cDNA microarray expression analysis as a reliable systematic instrument to complete the list of candidate genes that may play a role in exhaustive exercise-induced modulation of the immune response.

CDNA-microarray analysis as a research tool for expression profiling in human peripheral blood following exercise.

Exhausting endurance exercise has strong effects on the immune system. Changes have been shown in the cellular composition of peripheral blood and in gene expression within those cells. In this study, custom-made cDNA microarrays focused on inflammation were used to analyze gene expression blood cells obtained from eight half-marathon runners before (t0), immediately after (t1) and 24 hours after exercise (t2). The microarrays that were used contained 384 different cDNAs spotted in triplicate. Differentially-regulated gene expression was analyzed using a simple rule-based clustering. Comparing t1 vs. t0, and t2 vs. t0, 36 and 21 sequences respectively, showed a consistent pattern of changes in all eight athletes. Taken together, the pattern of these modified genes can be viewed as a "gene expression fingerprint" for each time point in response to a half marathon. The known and novel genes identified here represent targets for further molecular characterization of the complex reaction of the body to an exhaustive challenge. These data suggest that gene expression fingerprints can serve as a powerful research tool to design novel strategies for diagnosis and treatment of exercise related injury and stress.

Regional patterns of gene expression in human and chimpanzee brains.

We have analyzed gene expression in various brain regions of humans and chimpanzees. Within both human and chimpanzee individuals, the transcriptomes of the cerebral cortex are very similar to each other and differ more between individuals than among regions within an individual. In contrast, the transcriptomes of the cerebral cortex, the caudate nucleus, and the cerebellum differ substantially from each other. Between humans and chimpanzees, 10% of genes differ in their expression in at least one region of the brain. The majority of these expression differences are shared among all brain regions. Whereas genes encoding proteins involved in signal transduction and cell differentiation differ significantly between brain regions within individuals, no such pattern is seen between the species. However, a subset of genes that show expression differences between humans and chimpanzees are distributed nonrandomly across the genome. Furthermore, genes that show an elevated expression level in humans are statistically significantly enriched in regions that are recently duplicated in humans.