The transCampus Metabolic Training Programme Explores the Link of SARS-CoV-2 Virus to Metabolic Disease.

Currently, we are experiencing a true pandemic of a communicable disease by the virus SARS-CoV-2 holding the whole world firmly in its grasp. Amazingly and unfortunately, this virus uses a metabolic and endocrine pathway via ACE2 to enter our cells causing damage and disease. Our international research training programme funded by the German Research Foundation has a clear mission to train the best students wherever they may come from to learn to tackle the enormous challenges of diabetes and its complications for our society. A modern training programme in diabetes and metabolism does not only involve a thorough understanding of classical physiology, biology and clinical diabetology but has to bring together an interdisciplinary team. With the arrival of the coronavirus pandemic, this prestigious and unique metabolic training programme is facing new challenges but also new opportunities. The consortium of the training programme has recognized early on the need for a guidance and for practical recommendations to cope with the COVID-19 pandemic for the community of patients with metabolic disease, obesity and diabetes. This involves the optimal management from surgical obesity programmes to medications and insulin replacement. We also established a global registry analyzing the dimension and role of metabolic disease including new onset diabetes potentially triggered by the virus. We have involved experts of infectious disease and virology to our faculty with this metabolic training programme to offer the full breadth and scope of expertise needed to meet these scientific challenges. We have all learned that this pandemic does not respect or heed any national borders and that we have to work together as a global community. We believe that this transCampus metabolic training programme provides a prime example how an international team of established experts in the field of metabolism can work together with students from all over the world to address a new pandemic.

Predictors of pharmacological treatment outcomes with atomoxetine or methylphenidate in patients with attention-deficit/hyperactivity disorder from China, Egypt, Lebanon, Russian Federation, Taiwan, and United Arab Emirates.

BACKGROUND: The reduced availability of data from non-Western countries limits our ability to understand attention-deficit/hyperactivity disorder (ADHD) treatment outcomes, specifically, adherence and persistence of ADHD in children and adolescents. This analysis assessed predictors of treatment outcomes in a non-Western cohort of patients with ADHD treated with atomoxetine or methylphenidate. METHODS: Data from a 12-month, prospective, observational study in outpatients aged 6-17 years treated with atomoxetine (N = 234) or methylphenidate (N = 221) were analysed post hoc to determine potential predictors of treatment outcomes. Participating countries included the Russian Federation, China, Taiwan, Egypt, United Arab Emirates and Lebanon. Factors associated with remission were analysed with stepwise multiple logistic regression and classification and regression trees (CART). Cox proportional hazards models with propensity score adjustment assessed differences in atomoxetine persistence among initial-dose cohorts. RESULTS: In patients treated with atomoxetine who had available dosing information (N = 134), Cox proportional hazards revealed lower (< 0.5 mg/kg) initial dose was significantly associated with shorter medication persistence (p < 0.01). multiple logistic regression analysis revealed greater rates of remission for atomoxetine-treated patients were associated with age (older), country (United Arab Emirates) and gender (female) (all p < 0.05). CART analysis confirmed older age and lack of specific phobias were associated with greater remission rates. For methylphenidate, greater baseline weight (highly correlated with the age factor found for atomoxetine) and prior atomoxetine use were associated with greater remission rates. CONCLUSIONS: These findings may help clinicians assess factors upon initiation of ADHD treatment to improve course prediction, proper dosing and treatment adherence and persistence. TRIAL REGISTRATION: Observational study, therefore no registration.

Preclinical detection of Alzheimer's disease: hippocampal shape and volume predict dementia onset in the elderly.

Structural deformity of the hippocampus is characteristic of individuals with very mild and mild forms of dementia of the Alzheimer type (DAT). The purpose of this study was to determine whether a similar deformity of the hippocampus can predict the onset of dementia in nondemented elders. Using high dimensional diffeomorphic transformations of a neuroanatomical template, hippocampal volumes and surfaces were defined in 49 nondemented elders; the hippocampal surface was subsequently partitioned into three zones (i.e., lateral, superior and inferior-medial), which were proximal to the underlying CA1 subfield, CA2-4 subfields plus dentate gyrus, and subiculum, respectively. Annual clinical assessments using the Clinical Dementia Rating scale (CDR), where CDR 0 indicates no dementia and CDR 0.5 indicates very mild dementia, were then performed for a mean of 4.9 years (range 0.9-7.1 years) to monitor subjects who converted from CDR 0 to CDR 0.5. Inward variation of the lateral zone and left hippocampal volume significantly predicted conversion to CDR 0.5 in separate Cox proportional hazards models. When hippocampal surface variation and volume were included in a single model, inward variation of the lateral zone of the left hippocampal surface was selected as the only significant predictor of conversion. The pattern of hippocampal surface deformation observed in nondemented subjects who later converted to CDR 0.5 was similar to the pattern of hippocampal surface deformation previously observed to discriminate subjects with very mild DAT and nondemented subjects. These results suggest that inward deformation of the left hippocampal surface in a zone corresponding to the CA1 subfield is an early predictor of the onset of DAT in nondemented elderly subjects.

Labeled cortical mantle distance maps of the cingulate quantify differences between dementia of the Alzheimer type and healthy aging.

The cingulate gyri in 37 subjects with and without early dementia of the Alzheimer type (DAT) were studied by using MRI at 1.0 mm3 isotropic resolution. Groups were segregated into young controls (n = 10), age-matched normal controls (n = 10), very mild DAT (n = 8), and mild DAT (n = 9). By using automated Bayesian segmentation of the cortex and gray matter/white matter (GM/WM) isosurface generation, tissue compartments were labeled into gray, white, and cerebrospinal fluid as a function of distance from the GM/WM isosurface. Cortical mantle distance maps are generated profiling the GM volume and cortical mantle distribution as a function of distance from the cortical surface. Probabilistic tests based on generalizations of Wilcoxon-Mann-Whitney tests were applied to quantify cortical mantle distribution changes with normal and abnormal aging. We find no significant change between young controls and healthy aging as measured by the GM volume and cortical mantle distribution as a function of distance in both anterior and posterior regions of the cingulate. Significant progression of GM loss is seen in the very mild DAT and mild DAT groups in all areas of the cingulate. Posterior regions show both GM volume loss as well as significant cortical mantle distribution decrease with the onset of mild DAT. The "shape of the cortical mantle" as measured by the cortical mantle distance profiles manifests a pronounced increase in variability with mild DAT.

Template images for nonhuman primate neuroimaging: 1. Baboon.

Coregistration of functional brain images across many subjects offers several experimental advantages and is widely used for studies in humans. Voxel-based coregistration methods require a high-quality 3-D template image, preferably one that corresponds to a published atlas. Template images are available for human, but we could not find an appropriate template for neuroimaging studies in baboon. Here we describe the formation of a T1-weighted structural MR template image and a PET blood flow template, derived from 9 and 7 baboons, respectively. Custom software aligns individual MR images to the MRI template; human supervision is needed only to initially estimate any gross rotational misalignment. In these aligned individual images, internal subcortical fiducial points correspond closely to a photomicrographic baboon atlas with an average error of 1.53 mm. Cortical test points showed a mean error of 1.99 mm compared to the mean location for each point. Alignment of individual PET blood flow images directly to the PET template was compared to a two-step alignment process via each subject's MR image. The two transformations were identical within 0.41 mm, 0.54 degrees, and 1.0% (translation, rotation, and linear stretch; mean). These quantities provide a check on the validity of the alignment software as well as of the template images. The baboon structural MR and blood flow PET templates are available on the Internet (purl.org/net/kbmd/b2k) and can be used as targets for any image registration software.

Evaluation of a reduced MR imaging sequencing protocol in adult patients with stroke.

PURPOSE: To compare a reduced (three-sequence) magnetic resonance (MR) imaging protocol with a full (eight- to 10-sequence) MR imaging protocol in adults suspected of having stroke. MATERIALS AND METHODS: Six neuroradiologists interpreted a consecutive sample of 265 MR images in patients suspected of having stroke. Each read reduced-protocol images in a discrete series of 40 patients (one read images in only 15) and corresponding full-protocol images 1 month later (reduced/full protocol). Five of the readers each read images in 10 additional cases, five each as full/full and reduced/reduced protocol controls. kappa values between full and reduced protocols, reader assessment of protocol adequacy, confidence level, and need for additional sequences or examinations were evaluated. RESULTS: In the reduced/full protocol, the kappa value for detecting ischemia was 0.797; and that for detecting any clinically important abnormality, 0.635. Statistically similar kappa values were found with the full/full control design (kappa = 0.802 and 0.715, respectively). The full protocol was judged more adequate than the reduced protocol (2.0 of 5.0 points vs 1.6, P <.001) and generated greater diagnostic confidence (8.6 of 10.0 points vs 8.9, P =.01), less need for additional sequences (2.7 of 6.0 points vs 1.5, P <.001), and more requests for additional examinations (28.4% vs 36.3%). CONCLUSION: Disagreement between interpretations of reduced- and full-protocol images might be attributable to baseline-level intraobserver inconsistency, as demonstrated in control designs. A greater number of sequences did not lead to greater consistency.

Early DAT is distinguished from aging by high-dimensional mapping of the hippocampus. Dementia of the Alzheimer type.

OBJECTIVE: To determine the feasibility of using high-dimensional brain mapping (HDBM) to assess the structure of the hippocampus in older human subjects, and to compare measurements of hippocampal volume and shape in subjects with early dementia of the Alzheimer type (DAT) and in healthy elderly and younger control subjects. BACKGROUND: HDBM represents the typical structures of the brain via the construction of templates and addresses their variability by probabilistic transformations applied to the templates. Local application of the transformations throughout the brain (i.e., high dimensionality) makes HDBM especially valuable for defining subtle deformities in brain structures such as the hippocampus. METHODS: MR scans were obtained in 18 subjects with very mild DAT, 18 healthy elderly subjects, and 15 healthy younger subjects. HDBM was used to obtain estimates of left and right hippocampal volume and eigenvectors that represented the principal dimensions of hippocampal shape differences among the subject groups. RESULTS: Hippocampal volume loss and shape deformities observed in subjects with DAT distinguished them from both elderly and younger control subjects. The pattern of hippocampal deformities in subjects with DAT was largely symmetric and suggested damage to the CA1 hippocampal subfield. Hippocampal shape changes were also observed in healthy elderly subjects, which distinguished them from healthy younger subjects. These shape changes occurred in a pattern distinct from the pattern seen in DAT and were not associated with substantial volume loss. CONCLUSIONS: Assessments of hippocampal volume and shape derived from HDBM may be useful in distinguishing early DAT from healthy aging.

Dopamine D(1) agonist activates temporal lobe structures in primates.

Changes in the function of dopamine D(1)-influenced neuronal pathways may be important to the pathophysiology of several human diseases. We recently developed methods for averaging functional imaging data across nonhuman primate subjects; in this study, we apply this method for the first time to map brain responses to experimental dopamine agonists in vivo. Here we report the use of positron emission tomography (PET) in seven normal baboons to measure the regional cerebral blood flow (rCBF) responses produced by an acute dose of the dopamine D(1) full agonist SKF82958. The most significant rCBF increases were in bilateral temporal lobe, including amygdala and superior temporal sulcus (6-17%, P < 0.001). Blood flow decreased in thalamus, pallidum, and pons (4-7%, P = 0.001). Furthermore the rCBF responses were dose-dependent and had a half-life of approximately 30 min, similar to that reported for the drug's antiparkinsonian effects. Absolute whole-brain blood flow did not change, suggesting that these local changes in rCBF reflect neuronal rather than direct vascular effects of the agonist. The prominent temporal lobe response to a D(1) agonist supports and extends our recent observations that levodopa produces prominent amygdala activation both in humans and in other primates. We speculate that levodopa may exert its known effects on mood in humans through increased amygdala activity, mediated in part by D(1) receptors.

Comparison of computed tomography myelography and magnetic resonance imaging in the evaluation of cervical spondylotic myelopathy and radiculopathy.

STUDY DESIGN: A cross-sectional retrospective radiologic study. OBJECTIVES: To establish concordance rates between interpretations of computed tomography myelography and magnetic resonance imaging in patients with degenerative cervical spine disease. SUMMARY OF BACKGROUND DATA: Observed discrepancies in interpretation of computed tomography myelography and magnetic resonance imaging question the reliability of comparisons between these two methods. METHODS: This study blindly and randomly evaluated cervical computed tomography myelography and magnetic resonance imaging in 20 patients referred for clinically diagnosed cervical spondylotic radiculopathy, myelopathy, or both. The discovertebral joints, facet joints, lateral recesses, cord size, spinal canal, and neural foramina also were evaluated with graded scales. All results were subjected to the kappa statistic for strength of agreement. RESULTS: Agreement for interpretation of the discovertebral junction occurred in 144 of 240 sites (60%), indicating only moderately good intermethod concordance (kappa = 0.44). Intermethod agreement on the characterization of facet joint disease was only moderately good (143 of 160 sites; 89.4%; kappa = 0.52), and on characterization of lateral recess disease was poor (125 of 160 sites; 78.1%; kappa = 0.20). On degree of spinal canal compromise, there was agreement within one grade in 199 of 240 sites (82.9%; kappa = 0.42). Intermethod agreement on neural foraminal encroachment and cord size was only moderately good (kappa = 0.42 and 0.46, respectively). Computed tomography myelography tended to upgrade the spinal canal narrowing and neural foraminal encroachment. CONCLUSIONS: For most parameters of interpretation, the degree of concordance between computed tomography myelography and magnetic resonance imaging is only moderately good, with discrepancies noted especially in the differentiation of disc and bony pathology. These methods should be viewed as complementary studies.

Depression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depression.

This study takes advantage of continuing advances in the precision of magnetic resonance imaging (MRI) to quantify hippocampal volumes in a series of human subjects with a history of depression compared with controls. We sought to test the hypothesis that both age and duration of past depression would be inversely and independently correlated with hippocampal volume. A sample of 24 women ranging in age from 23 to 86 years with a history of recurrent major depression, but no medical comorbidity, and 24 case-matched controls underwent MRI scanning. Subjects with a history of depression (post-depressed) had smaller hippocampal volumes bilaterally than controls. Post-depressives also had smaller amygdala core nuclei volumes, and these volumes correlated with hippocampal volumes. In addition, post-depressives scored lower in verbal memory, a neuropsychological measure of hippocampal function, suggesting that the volume loss was related to an aspect of cognitive functioning. In contrast, there was no difference in overall brain size or general intellectual performance. Contrary to our initial hypothesis, there was no significant correlation between hippocampal volume and age in either post-depressive or control subjects, whereas there was a significant correlation with total lifetime duration of depression. This suggests that repeated stress during recurrent depressive episodes may result in cumulative hippocampal injury as reflected in volume loss.

Hippocampal morphometry in schizophrenia by high dimensional brain mapping.

Theories of the pathophysiology of schizophrenia have implicated the hippocampus, but controversy remains regarding hippocampal abnormalities in patients with schizophrenia. In vivo studies of hippocampal anatomy using high resolution magnetic resonance scanning and manual methods for volumetric measurement have yielded inconclusive results, perhaps because of the normal variability in hippocampal volume and the error involved in manual measurement techniques. To resolve this controversy, high dimensional transformations of a computerized brain template were used to compare hippocampal volumes and shape characteristics in 15 matched pairs of schizophrenia and control subjects. The transformations were derived from principles of general pattern matching and were constrained according to the physical properties of fluids. The analysis and comparison of hippocampal shapes based on these transformations were far superior to the comparison of hippocampal volumes or other global indices of hippocampal anatomy in showing a statistically significant difference between the two groups. In the schizophrenia subjects, hippocampal shape deformations were found to be localized to subregions of the structure that send projections to prefrontal cortex. The results of this study demonstrate that abnormalities of hippocampal anatomy occur in schizophrenia and support current hypotheses that schizophrenia involves a disturbance of hippocampal-prefrontal connections. These results also show that comparisons of neuroanatomical shapes can be more informative than volume comparisons for identifying individuals with neuropsychiatric diseases, such as schizophrenia.

Amygdala core nuclei volumes are decreased in recurrent major depression.

The amygdala is a key structure in the brain's integration of emotional meaning with perception and experience. Patients with depression have impaired functioning in emotional tasks involving the amygdala, and have abnormal resting amygdala blood flow. To better understand the anatomical basis for these functional changes we measured the volumes of the total amygdala and of the core amygdala nuclei in 20 patients with a history of depression and 20 pair-wise matched controls. Depressed subjects had bilaterally reduced amygdala core nuclei volumes and no significant differences in total amygdala volumes or in whole brain volumes. Since patients with a depression history have bilateral hippocampal volume reduction the volume loss in this closely related structure suggests a shared effect on both structures, potentially glucocorticoid-induced neurotoxicity mediated by the extensive reciprocal glutamatergic connections.

Baboon basal ganglia stereotaxy using internal MRI landmarks: validation and application to PET imaging.

PURPOSE: We report the residual anatomic error after a nine parameter visually guided registration of MR images with a baboon brain atlas to validate a stereotactic method for use in PET studies. METHOD: MPRAGE images of brain in six baboons and one nemestrina monkey were placed in atlas space using internal landmarks and proportional measurements. An expert noted the location of 23 subcortical test points in the transformed images and in the atlas. RESULTS: The average absolute error at the test points was 1.62 mm. At the extremes of the brain surface, there was more variability. PET images could be combined across animals in a common atlas space. CONCLUSION: There is minimal subcortical error attributable to anatomic variability after this method of transforming MR images of baboon to stereotactic space. This method provides a useful tool for intrasubject PET baboon studies as well as "bootstrapping" for more refined methods.

PET measurement of dopamine D2 receptor-mediated changes in striatopallidal function.

This study was designed to validate an in vivo measurement of the functional sensitivity of basal ganglia neuronal circuits containing dopamine D2 receptors. We hypothesized that a D2 agonist would decrease striatopallidal neuronal activity, and hence regional cerebral blood flow (rCBF) over the axon terminals in the globus pallidus. Quantitative pallidal blood flow was measured using positron emission tomography (PET) with bolus injections of H215O and arterial sampling in six baboons before and after intravenous administration of the selective D2 agonist U91356a. We also tested whether the response to U91356a was modified by previous acute administration of various antagonists. Another baboon had serial measurements of blood flow under identical conditions, but received no dopaminergic drugs. In all animals that received U91356a, pallidal flow decreased in a dose-related manner. Global CBF had a similar response, but the decline in pallidal flow was greater in magnitude and remained significant after accounting for the global effect. A D2 antagonist, but not antagonists of D1, serotonin-2, or peripheral D2 receptors, prevented this decrease. This work demonstrates and validates an in vivo measure of the sensitivity of D2-mediated basal ganglia pathways. It also supports the hypothesis that activation of the indirect striatopallidal pathway, previously demonstrated using nonselective D2-like agonists, can be mediated specifically by D2 receptors. We speculate that the U91356a-PET technique may prove useful in detecting functional abnormalities of D2-mediated dopaminergic function in diseases such as parkinsonism, dystonia, Tourette syndrome, or schizophrenia.

Three-dimensional hippocampal MR morphometry with high-dimensional transformation of a neuroanatomic atlas.

PURPOSE: To test automated three-dimensional magnetic resonance (MR) imaging morphometry of the human hippocampus, to determine the potential gain in precision compared with conventional manual morphometry. MATERIAL AND METHODS: A canonical three-dimensional MR image atlas was used as a deformable template and automatically matched to three-dimensional MR images of 10 individuals (five healthy and five schizophrenic subjects). A subvolume containing the hippocampus was defined by using 16 landmarks that constrained the automated search for hippocampal boundaries. Transformation of the hippocampus template was automatically performed by using global pattern matching through a sequence of low-then high-dimensional translations, rotations, and scalings. RESULTS: The average test-retest volume difference measured with the automatic method was 3.1%, compared with the manual test-retest difference of 7.1%. Correlation between automated and manually determined volumes demonstrated the validity of the automated technique (intraclass correlation coefficient = .86). CONCLUSION: The automated method estimates hippocampal volumes with less variability (ie, lower variance) than that of manual out-lining.

Stereological MRI volumetry of the frontal lobe.

Stereology was used to measure frontal lobe volume on magnetic resonance imaging (MRI) scans in a multi-observer repeated-measures trial in 17 adults. Prior to measurement, MR image volumes were reoriented into coronal sections perpendicular to the bicommissural plane. Three observers blinded to subject identify repeatedly used fixed grid stereology to estimate frontal lobe volumes, defined as all sections of the frontal lobe anterior to the anterior commissure. The lateral ventricles were excluded. Stereological measurement yielded high repeatability and precision, and was time efficient for the raters. The coefficient of error was 0.03. The inter-rater correlation coefficient = 0.95 for three raters; intra-rater correlation coefficients = 0.95-0.98. A comparison was made between stereological and traditional edge tracing measurement of the frontal lobe volumes. The overall correlation between the two methods was 0.95. The use of internal landmarks to define orientation and 3-D orthogonal views to define frontal lobe boundaries on 3-D images was critical to obtaining repeatable measurements. Frontal lobe volumetry by brain MR used to estimate small differences postulated to occur in certain psychiatric and neurologic disorders requires high precision and repeatability. Stereology, a semi-automated method, can reliably estimate frontal lobe volumes. This method may distinguish small frontal lobe volume differences within individuals and between groups.

Comparison of clinical evaluation and computed tomographic diagnostic accuracy for tumors of the larynx and hypopharynx.

Ninety-five patients with laryngeal and hypopharyngeal cancer were examined and staged preoperatively by clinical evaluation (CE) and computed tomography (CT). The CE and CT staging were compared to each other and to the pathologic (PT) staging of the tumors. The CT staging showed high accuracy in staging transglottic (88%), supraglottic (68%), and oropharyngeal tumors invading the larynx (68%) when compared to the PT findings. The CT staging was less effective in evaluating glottic tumors (46%), both overstaging (12%) and understaging (20%) cases. Combined CE-CT evaluation showed higher accuracy in staging all tumors (84%) compared to CE alone (52%) or CT alone (68%). The findings suggest that combined CE-CT should be used to evaluate laryngeal and hypopharyngeal tumors.

Hippocampal atrophy in recurrent major depression.

Hippocampal volumes of subjects with a history of major depressive episodes but currently in remission and with no known medical comorbidity were compared to matched normal controls by using volumetric magnetic resonance images. Subjects with a history of major depression had significantly smaller left and right hippocampal volumes with no differences in total cerebral volumes. The degree of hippocampal volume reduction correlated with total duration of major depression. In addition, large (diameter > or = 4.5 mm)-hippocampal low signal foci (LSF) were found within the hippocampus, and their number also correlated with the total number of days depressed. These results suggest that depression is associated with hippocampal atrophy, perhaps due to a progressive process mediated by glucocorticoid neurotoxicity.

Craniosynostosis: diagnostic imaging with three-dimensional CT presentation.

PURPOSE: To measure diagnostic performance and preference of two three-dimensional CT reconstruction modalities (voxel-gradient and surface-projection) displayed two ways (conventional and unwrapped) in craniosynostosis confirmed by surgical inspection and histologic analysis of resected sutures. METHODS: High-resolution 2-mm contiguous CT sections were obtained and three-dimensional reconstruction images generated for 25 infants and children with skull deformities before surgical treatment of craniosynostosis. Two pediatric radiologists and two neuroradiologists first ranked images by their own preferences for diagnostic use. Then they diagnosed craniosynostosis from images presented in random order and blinded. The standard of reference was inspection during surgery and histologic evaluation of excised sutures. Finally, reviewers repeated their subjective preference tests. RESULTS: The least experienced radiologist had 100% sensitivity for all imaging modalities and specificities ranging from 43% to 83%. The two most experienced radiologists performed nearly identically, with sensitivities of 96% and specificities of 100%. After performing diagnostic tasks using all image types, all radiologists preferred conventional surface projections. CONCLUSION: Experienced readers can achieve nearly perfect diagnostic performance using the latest three-dimensional CT reconstruction images, making it a contribution to the diagnostic process. Although performance is nearly identical for all modalities, readers strongly prefer conventionally presented surface-projection images.

Interactive segmentation of cerebral gray matter, white matter, and CSF: photographic and MR images.

Digital photography of postmortem brain slices was compared with magnetic resonance imaging (MRI) for morphological analysis of human brain atrophy. In this study, we used two human brains obtained at autopsy: a cognitively defined nondemented control (70-yr-old male) and a demented Alzheimer's disease (AD) subject (82-yr-old female). For each of two brains, interactive manual image segmentation was performed by two observers on two image sets: (a) four coronal T1-weighted MR images (5 mm slices); and (b) four digitized photographic images from comparable rostrocaudal levels. Microcomputer image analysis software was used to measure the areas of three segmented cerebral compartments--gray matter (GM), white matter (WM) and CSF--for both image types. Resegmentation error was defined as the absolute difference between the areas derived from two segmentation trials divided by the value from trial 1 and multiplied by 100. This yielded the percent difference between the area measurements from the two trials. We found intra-observer agreement was better (error rates 1-18%) than inter-observer agreement (3-70%) with best agreement for WM and least for CSF, the smallest object class. MRI overestimated GM area relative to digitized photographs in the control but not the AD brain. The results define limitations of manual image segmentations and comparison of MRI with pathologic section photographic images.