Faculty Bibliography

The cerebral deposition of amyloid beta-peptide, a central event in Alzheimer's disease (AD) pathogenesis, begins several years before the onset of clinical symptoms. Noninvasive detection of AD pathology at this initial stage would facilitate intervention and enhance treatment success. In this study, high-field MRI was used to detect changes in regional brain MR relaxation times in three types of mice: 1). transgenic mice (PS/APP) carrying both mutant genes for amyloid precursor protein (APP) and presenilin (PS), which have high levels and clear accumulation of beta-amyloid in several brain regions, starting from 10 weeks of age; 2). transgenic mice (PS) carrying only a mutant gene for presenilin (PS), which show subtly elevated levels of Abeta-peptide without beta-amyloid deposition; and 3). nontransgenic (NTg) littermates as controls. The transverse relaxation time T(2), an intrinsic MR parameter thought to reflect impaired cell physiology, was significantly reduced in the hippocampus, cingulate, and retrosplenial cortex, but not the corpus callosum, of PS-APP mice compared to NTg. No differences in T(1) values or proton density were detected between any groups of mice. These results indicate that T(2) may be a sensitive marker of abnormalities in this transgenic mouse model of AD

We describe the design of finite-size linear-phase separable kernels for differentiation of discrete multidimensional signals. The problem is formulated as an optimization of the rotation-invariance of the gradient operator, which results in a simultaneous constraint on a set of one-dimensional low-pass prefilter and differentiator filters up to the desired order. We also develop extensions of this formulation to both higher dimensions and higher order directional derivatives. We develop a numerical procedure for optimizing the constraint, and demonstrate its use in constructing a set of example filters. The resulting filters are significantly more accurate than those commonly used in the image and multidimensional signal processing literature

Objective methods for assessing perceptual image quality traditionally attempted to quantify the visibility of errors (differences) between a distorted image and a reference image using a variety of known properties of the human visual system. Under the assumption that human visual perception is highly adapted for extracting structural information from a scene, we introduce an alternative complementary framework for quality assessment based on the degradation of structural information. As a specific example of this concept, we develop a Structural Similarity Index and demonstrate its promise through a set of intuitive examples, as well as comparison to both subjective ratings and state-of-the-art objective methods on a database of images compressed with JPEG and JPEG2000

Multiple sclerosis (MS) has traditionally been viewed as an inflammatory demyelinating white matter (WM) disease of the central nervous system. However, recent pathology and MRI studies have shown lesions in the gray matter (GM) as well. To ascertain the extent of GM involvement, we obtained with nonlocalizing proton MR spectroscopy the concentration of N-acetylaspartate (NAA), a metabolite found almost exclusively in neuronal cells, T2-lesion loads, and GM and WM fractions in the entire brain of 71 relapsing-remitting (RR) MS patients (51 women, 20 men, 25-55 years old) and 41 healthy controls (27 women, 14 men, 23-55 years old). The average whole-brain NAA (WBNAA) difference between the patients and the controls was -2.9 mM (-22%, P < 0.0001); range: +1.2 to -7.8 mM (+8% to -63%). The patients' median T2 lesion volume was 5.5 (range: 0.140-28) cm(3). GM and WM comprised 50.4 +/- 3.8% and 30.4 +/- 5.0% (mean +/- standard deviation), respectively, of the total brain volume in the patients; 53.8 +/- 3.7% and 35.4 +/- 4.7% in the controls. Because WM and GM constitute approximately 40% and 60% of the brain parenchyma, respectively, and the NAA concentration in the former is 2/3 of the latter, WBNAA loss greater than 40% x 2/3 = 27% cannot be explained in terms of WM (axonal) pathology alone and must include widespread GM (neuronal) deficits. Therefore, the concept of MS, even at its earlier stages, as a WM disease might need to be reexamined

A functional magnetic resonance imaging (fMRI) study was conducted during which seven subjects carried out naturalistic tactile object recognition (TOR) of real objects. Activation maps, conjunctions across subjects, were compared between tasks involving TOR of common real objects, palpation of 'nonsense' objects, and rest. The tactile tasks involved similar motor and sensory stimulation, allowing higher tactile recognition processes to be isolated. Compared to nonsense object palpation, the most prominent activation evoked by TOR was in secondary somatosensory areas in the parietal operculum (SII) and insula, confirming a modality-specific path for TOR. Prominent activation was also present in medial and lateral secondary motor cortices, but not in primary motor areas, supporting the high level of sensory and motor integration characteristic of object recognition in the tactile modality. Activation in a lateral occipitotemporal area associated previously with visual object recognition may support cross-modal collateral activation. Finally, activation in medial temporal and prefrontal areas may reflect a common final pathway of modality-independent object recognition. This study suggests that TOR involves a complex network including parietal and insular somatosensory association cortices, as well as occipitotemporal visual areas, prefrontal, and medial temporal supramodal areas, and medial and lateral secondary motor cortices. It confirms the involvement of somatosensory association areas in the recognition component of TOR, and the existence of a ventrolateral somatosensory pathway for TOR in intact subjects. It challenges the results of previous studies that emphasize the role of visual cortex rather than somatosensory association cortices in higher-level somatosensory cognition

Schwann cell factor 1 (SC1), a p75 neurotrophin receptor-interacting protein, is a member of the positive regulatory/suppressor of variegation, enhancer of zeste, trithorax (PR/SET) domain-containing zinc finger protein family, and it has been shown to be regulated by serum and neurotrophins. SC1 shows a differential cytoplasmic and nuclear distribution, and its presence in the nucleus correlates strongly with the absence of bromodeoxyuridine (BrdU) in these nuclei. Here, we investigated potential transcriptional activities of SC1 and analyzed the function of its various domains. We show that SC1 acts as a transcriptional repressor when it is tethered to Gal4 DNA-binding domain. The repressive activity requires a trichostatin A-sensitive histone deacetylase (HDAC) activity, and SC1 is found in a complex with HDACs 1, 2, and 3. Transcriptional repression exerted by SC1 requires the presence of its zinc finger domains and the PR domain. Additionally, these two domains are involved in the efficient block of BrdU incorporation by SC1. The zinc finger domains are also necessary to direct SC1's nuclear localization. Lastly, SC1 represses the promoter of a promitotic gene, cyclin E, suggesting a mechanism for how growth arrest is regulated by SC1

Although cell culture studies have implicated the presence of vesicle proteins in mediating the release of glutamate from astrocytes, definitive proof requires the identification of the glutamate release mechanism and the localization of this mechanism in astrocytes at synaptic locales. In cultured murine astrocytes we show an array of vesicle proteins, including SNARE proteins, and vesicular glutamate transporters that are required to fill vesicles with glutamate. Using immunocytochemistry and single-cell multiplex reverse transcription-PCR we demonstrate the presence of these proteins and their transcripts within astrocytes freshly isolated from the hippocampus. Moreover, immunoelectron microscopy demonstrates the presence of VGLUT1 in processes of astrocytes of the hippocampus. To determine whether calcium-dependent glutamate release is mediated by exocytosis, we expressed the SNARE motif of synaptobrevin II to prevent the formation of SNARE complexes, which reduces glutamate release from astrocytes. To further determine whether vesicular exocytosis mediates calcium-dependent glutamate release from astrocytes, we performed whole cell capacitance measurements from individual astrocytes and demonstrate an increase in whole cell capacitance, coincident with glutamate release. Together, these data allow us to conclude that astrocytes in situ express vesicle proteins necessary for filling vesicles with the chemical transmitter glutamate and that astrocytes release glutamate through a vesicle- or fusion-related mechanism.

Radial glial cells function during CNS development as neural progenitors, although their precise contribution to neurogenesis remains controversial. Recent work has argued that regional differences may exist regarding the neurogenic potential of radial glia. Here, we show that the vast majority of neurons in all brain regions derive from radial glia. Cre/loxP fate mapping and clonal analysis demonstrate that radial glia throughout the CNS serve as neuronal progenitors and that radial glia within different regions of the CNS pass through their neurogenic stage of development at distinct time points. Thus, radial glial populations within different CNS regions are not heterogeneous with regard to their potential to generate neurons versus glia