David S. Lee

Cluster of genes encoding the major egg envelope protein of zebrafish.

The proteins of fish egg envelopes are encoded by genes that are closely related to the genes for human zona pellucida proteins. A cluster of three genes coding for an egg envelope protein was isolated from the zebrafish, Danio rerio. The three genes, zp2a, zp2b, and zp2c, are located within an 11 kb region and are each comprised of eight exons spanning 1.85 kb. The exon–intron structures of the genes are nearly identical; however, their deduced amino acid sequences diverge at exon 7 (zp2b and zp2c from zp2a) and exon 8 (zp2c from zp2b). Exons 2–7 have a structural organization similar to exons in the carboxy‐terminal half of the human zona pellucida ZP1, ZP2, and ZPB genes, suggesting they arose from a common ancestral gene. Sequence comparisons indicate that the deduced zebrafish proteins are most closely related to human ZPB. Zebrafish mRNAs coding for each of the three ZP2 variants have been found either as full‐length cDNAs or expressed sequence tags. Distinct from the wf♀ gene of winter flounder which we first reported (Lyons et al., 1993 : J Biol Chem 268:21351–21358), expression of the zebrafish zp2 genes was found to be ovary‐specific, instead of liver‐specific, and the promoter regions of zp2a and zp2b, while different, both contained E‐box sequences (CANNTG) that have been demonstrated to be essential for coordination of zona pellucida gene expression in mammalian oocytes. Mixed peptide sequence analysis was used to identify the major polypeptide component of isolated zebrafish egg envelopes as the zp2 gene product. Mol. Reprod. Dev. 58:4–14, 2001.

The diffeomorphometry of temporal lobe structures in preclinical Alzheimer's disease

This paper examines morphometry of MRI biomarkers derived from the network of temporal lobe structures including the amygdala, entorhinal cortex and hippocampus in subjects with preclinical Alzheimers disease (AD). Based on template-centered population analysis, it is demonstrated that the structural markers of the amygdala, hippocampus and entorhinal cortex are statistically significantly different between controls and those with preclinical AD. Entorhinal cortex is the most strongly significant based on the linear effects model (p < .0001) for the high-dimensional vertex- and Laplacian-based markers corresponding to localized atrophy. The hippocampus also shows significant localized high-dimensional change (p < .0025) and the amygdala demonstrates more global change signaled by the strength of the low-dimensional volume markers. The analysis of the three structures also demonstrates that the volume measures are only weakly discriminating between preclinical and control groups, with the average atrophy rates of the volume of the entorhinal cortex higher than amygdala and hippocampus. The entorhinal cortex thickness also exhibits an atrophy rate nearly a factor of two higher in the ApoE4 positive group relative to the ApoE4 negative group providing weak discrimination between the two groups.

Amygdalar atrophy in symptomatic Alzheimer's disease based on diffeomorphometry: the BIOCARD cohort.

This article examines the diffeomorphometry of magnetic resonance imaging-derived structural markers for the amygdala, in subjects with symptomatic Alzheimers disease (AD). Using linear mixed-effects models we show differences between those with symptomatic AD and controls. Based on template centered population analysis, the distribution of statistically significant change is seen in both the volume and shape of the amygdala in subjects with symptomatic AD compared with controls. We find that high-dimensional vertex based markers are statistically more significantly discriminating (p < 0.00001) than lower-dimensional markers and volumes, consistent with comparable findings in presymptomatic AD. Using a high-field 7T atlas, significant atrophy was found to be centered in the basomedial and basolateral subregions, with no evidence of centromedial involvement.

Catheter-directed Thrombolytic Therapy for Limb Ischemia: Current Status and Controversies

Absence of urokinase from the United States market for the past 4 years has resulted in increasing experience with other plasminogen activators in catheter-directed thrombolytic therapy. The differences in the pharmacologic properties and biologic behavior of these agents may translate into clinical outcomes that are distinct. Some of these manifestations can be predicted based on the existing large clinical trials in the acute myocardial infarction literature. However, because of the fundamental differences in techniques and thrombolytic regimens, extrapolation of the coronary data may not always predict the performance of these agents in peripheral catheter-directed fibrinolysis. In this article, the current status of the available lytic agents in the treatment of limb ischemia is reviewed.

Network Neurodegeneration in Alzheimer's Disease via MRI Based Shape Diffeomorphometry and High-Field Atlasing.

This paper examines MRI analysis of neurodegeneration in Alzheimer’s Disease (AD) in a network of structures within the medial temporal lobe using diffeomorphometry methods coupled with high-field atlasing in which the entorhinal cortex is partitioned into eight subareas. The morphometry markers for three groups of subjects (controls, preclinical AD, and symptomatic AD) are indexed to template coordinates measured with respect to these eight subareas. The location and timing of changes are examined within the subareas as it pertains to the classic Braak and Braak staging by comparing the three groups. We demonstrate that the earliest preclinical changes in the population occur in the lateral most sulcal extent in the entorhinal cortex (alluded to as transentorhinal cortex by Braak and Braak), and then proceeds medially which is consistent with the Braak and Braak staging. We use high-field 11T atlasing to demonstrate that the network changes are occurring at the junctures of the substructures in this medial temporal lobe network. Temporal progression of the disease through the network is also examined via changepoint analysis, demonstrating earliest changes in entorhinal cortex. The differential expression of rate of atrophy with progression signaling the changepoint time across the network is demonstrated to be signaling in the intermediate caudal subarea of the entorhinal cortex, which has been noted to be proximal to the hippocampus. This coupled to the findings of the nearby basolateral involvement in amygdala demonstrates the selectivity of neurodegeneration in early AD.

Endovascular Model of Rabbit Hindlimb Ischemia: A Platform to Evaluate Therapeutic Angiogenesis

PURPOSE Current animal hindlimb ischemia models involve surgical ligation of the femoral artery and delivery of therapeutic angiogenic agents into the adductor compartment. The authors hypothesize that an endovascular model of hindlimb ischemia would be a more appropriate platform, closely resembling atherosclerosis by occluding the vessel from within, causing less inflammation, wound healing and subsequent collateralization. MATERIALS AND METHODS The left superficial femoral artery in 17 rabbits was occluded by endovascular coil embolization (n=9) or surgical ligation (n=8). Animals (n=3; in each group) were sacrificed on day 3 to determine the arteriolar luminal area, number of arterioles, microsphere determined perfusion, and degree of inflammation. On day 28, the remaining animals underwent calf blood pressure measurements and angiography to determine the number of collaterals and diameter of vessels supplying the hindlimb. RESULTS Immediate postprocedure (day 0) and presacrifice (day 3 or 28) occlusion rates were 89% (eight of nine rabbits) and 100% for the endovascular model; 100% and 100% for the surgical model, respectively. Hindlimb paralysis and muscle atrophy was found in one surgical animal. On day 3, there was an increase in hindlimb perfusion (surgery, 0.04+/-0.01; endovascular, 0.02+/-0.01; P=.02), an increase in arteriolar luminal area (surgery, 481 microm+/-240; endovascular, 345 microm+/-151; P=.04), and a trend toward more inflammation (surgery, 5.5+/-3.8; endovascular, 2.5+/-3.0; P=.08) in the surgical group. There was no difference in number of vessels between both groups. On day 28 there was no difference in the calf blood pressure ratios or in the number of collaterals. However, there was enlargement of the distal profunda femoris artery, the vessel closest to the surgical incision, in the surgical group (L/R ratio: immediate post-occlusion, 1.06+/-0.11; day 28, 1.27+/-0.08; P=.02). CONCLUSION The endovascular model was efficacious in providing occlusion of the superficial femoral artery, and induced less of an arteriogenic response compared with the surgical model. The authors believe that this endovascular model is a superior platform for studying therapeutic angiogenic agents.

Linking white matter and deep gray matter alterations in premanifest Huntington disease.

Huntington disease (HD) is a fatal progressive neurodegenerative disorder for which only symptomatic treatment is available. A better understanding of the pathology, and identification of biomarkers will facilitate the development of disease-modifying treatments. HD is potentially a good model of a neurodegenerative disease for development of biomarkers because it is an autosomal-dominant disease with complete penetrance, caused by a single gene mutation, in which the neurodegenerative process can be assessed many years before onset of signs and symptoms of manifest disease. Previous MRI studies have detected abnormalities in gray and white matter starting in premanifest stages. However, the understanding of how these abnormalities are related, both in time and space, is still incomplete. In this study, we combined deep gray matter shape diffeomorphometry and white matter DTI analysis in order to provide a better mapping of pathology in the deep gray matter and subcortical white matter in premanifest HD. We used 296 MRI scans from the PREDICT-HD database. Atrophy in the deep gray matter, thalamus, hippocampus, and nucleus accumbens was analyzed by surface based morphometry, and while white matter abnormalities were analyzed in (i) regions of interest surrounding these structures, using (ii) tractography-based analysis, and using (iii) whole brain atlas-based analysis. We detected atrophy in the deep gray matter, particularly in putamen, from early premanifest stages. The atrophy was greater both in extent and effect size in cases with longer exposure to the effects of the CAG expansion mutation (as assessed by greater CAP-scores), and preceded detectible abnormalities in the white matter. Near the predicted onset of manifest HD, the MD increase was widespread, with highest indices in the deep and posterior white matter. This type of in-vivo macroscopic mapping of HD brain abnormalities can potentially indicate when and where therapeutics could be targeted to delay the onset or slow the disease progression.

Velocity measurement of microvessels using phase‐contrast magnetic resonance angiography at 7 tesla MRI

The purpose of this study was to measure the velocity and direction of blood flow in microvessels, such as lenticulostriate arteries (LSAs), using PC MRA.

Morphometry of the amygdala in schizophrenia and psychotic bipolar disorder

Volumetric studies suggest smaller amygdalae in subjects with schizophrenia (SZ) than with bipolar disorder (BP). We use morphometry to identify subregions of amygdala differentially affected in SZ and psychotic BP. Based on template centered population analysis, the shape of the amygdala in psychotic BP differs from SZ (pleft=0.044, pright=0.042). Using a high-field 7 T atlas, the bilateral basolateral, basomedial and centromedial subregions and the right lateral subregion were significantly atrophied in SZ compared to psychotic BP (p<0.02). These results suggest that change in shape of amygdala may represent a morphologic feature distinguishing SZ from psychotic BP.

Computational Anatomy Gateway: Leveraging XSEDE Computational Resources for Shape Analysis

Computational Anatomy (CA) is a discipline focused on the quantitative analysis of the variability in biological shape. The Large Deformation Diffeomorphic Metric Mapping (LDDMM) is the key algorithm which assigns computable descriptors of anatomical shapes and a metric distance between shapes. This is achieved by describing populations of anatomical shapes as a group of diffeomorphic transformations applied to a template, and using a metric on the space of diffeomorphisms. LDDMM is being used extensively in the neuroimaging (www.mristudio.org) and cardiovascular imaging (www.cvrgrid.org) communities. There are two major components involved in shape analysis using this paradigm. First is the estimation of the template, and second is calculating the diffeomorphisms mapping the template to each subject in the population. Template estimation is a computationally expensive problem, which involves an iterative process, where each iteration calculates one diffeomorphism for each target. These can be calculated in parallel and independently of each other, and XSEDE is providing the resources, in particular those provided by the cluster Stampede, that make these computations for large populations possible. Mappings from the estimated template to each subject can also be run in parallel. In addition, the use of NVIDIA Tesla GPUs available on Stampede present the possibility of speeding up certain convolution-like calculations which lend themselves well to the General Purpose GPU computation model. We are also exploring the use of the available Xeon Phi Co-processors to increase the efficiency of our codes. This will have a huge impact on both the neuroimaging and cardiac imaging communities as we bring these shape analysis tools online for use by these communities through our webservice (www.mricloud.org), with the XSEDE Computational Anatomy Gateway providing the resources to handle the computational demands for large populations.