Faculty Bibliography

During embryogenesis, the lateral cortical stream (LCS) emerges from the corticostriatal border (CSB), the boundary between the developing cerebral cortex and striatum. The LCS is comprised of a mix of pallial- and subpallial-derived neural progenitor cells that migrate to the developing structures of the basal telencephalon, most notably the piriform cortex and amygdala. Using a combination of in vitro and in vivo approaches, we analyzed the timing, composition, migratory modes, origin, and requirement of the homeodomain-containing transcription factor Gsh2 (genomic screened homeobox 2) in the development of this prominent migratory stream. We reveal that Pax6 (paired box gene 6)-positive pallial-derived and Dlx2 (distal-less homeobox 2)-positive subpallial-derived subpopulations of LCS cells are generated in distinct temporal windows during embryogenesis. Furthermore, our data indicate the CSB border not only is comprised of separate populations of pallial- and subpallial-derived progenitors that contribute to the LCS but also a subpopulation of cells coexpressing Pax6 and Dlx2. Moreover, despite migrating along a route outlined by a cascade of radial glia, the Dlx2-positive population appears to migrate primarily in an apparent chain-like manner, with LCS migratory cells being generated locally at the CSB with little contribution from other subpallial structures such as the medial, lateral, or caudal ganglionic eminences. We further demonstrate that the generation of the LCS is dependent on the homeodomain-containing gene Gsh2, revealing a novel requirement for Gsh2 in telencephalic development

BACKGROUND AND PURPOSE: Glial cancer cells can be found well beyond the MR imaging T2 signal-intensity hyperintensity. To quantify the extent of the diffuse microstructural tissue damage possibly due to the presence of these satellite tumor cells, we investigated the relationships between global metabolic and microstructural abnormalities in the normal-appearing brain regions of patients with newly diagnosed glioma. MATERIAL AND METHODS: Ten patients (6 men, 4 women) with radiologically suspected untreated supratentorial glial tumors and 9 healthy controls (5 men, 4 women) were studied with T1- and T2-weighted MR imaging, diffusion-weighted echo-planar MR imaging, and whole-brain N-acetylaspartate (WBNAA) proton MR spectroscopy. The relationship between the WBNAA concentration, the mean diffusivity (MD), and fractional anisotropy (FA) values in a large contralateral normal-appearing white matter (NAWM) brain region was investigated with the Spearman rank correlation test. RESULTS: WBNAA values were significantly lower (P < .001) in patients (9.7 +/- 1.7 mmol/L) than controls (13.1 +/- 1.1 mmol/L). MD values were higher (P = .0001) in patients (0.95 +/- 0.07 mm(2)s(-1)) than in controls (0.61 +/- 0.04 mm(2)s(-1)). FA values did not differ between patients (0.42 +/- 0.08) and controls (0.43 +/- 0.041). A strong inverse correlation between WBNAA and MD (r = -0.88, P = .0008) was found in the patients but not in controls (r = 0.012, P = .975). CONCLUSION: The correlation between the WBNAA and MD in the contralateral NAWM suggests that the microstructural damage possibly related to the presence of infiltrative tumor cells contributes to WBNAA decline in these patients

To trigger action potentials in neurons, most investigators use electrical or chemical stimulation. Here we describe an optical stimulation method based on semi-synthetic light-activated ion channels. These SPARK (synthetic photoisomerizable azobenzene-regulated K(+)) channels consist of a synthetic azobenzene-containing photoswitch and a genetically modified Shaker K(+) channel protein. SPARK channels with a wild-type selectivity filter elicit hyperpolarization and suppress action potential firing when activated by 390 nm light. A mutation in the pore converts the K(+)-selective Shaker channel into a nonselective cation channel. Activation of this modified channel with the same wavelength of light elicits depolarization of the membrane potential. Expression of these depolarizing SPARK channels in neurons allows light to rapidly and reversibly trigger action potential firing. Hence, hyper- and depolarizing SPARK channels provide a means for eliciting opposite effects on neurons in response to the same light stimulus.

s Background. Treatment of patients receiving hemodialysis who have anemia varies considerably despite the availability of established practice guidelines from the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI). Objective. To compare actual use of erythropoietin (EPO) and intravenous (IV) iron with that recommended in KDOQI guidelines. Methods. A budget impact model was used to calculate costs per member per month (PMPM) for actual practice versus recommended practice were calculated using Medicare reimbursement rates for EPO and IV iron. A sensitivity analysis tested the impact of varying the recommended dosages by 50%. Results. For EPO, a net savings PMPM of $257 (if administered by IV) or $252 (if administered subcutaneously) could be achieved with adherence to KDOQI guidelines. Adherence to KDOQI recommendations for IV iron would increase Medicare reimbursements for this drug by an estimated $6 PMPM. Sensitivity analysis revealed a significant potential savings even if the dose of EPO used in practice was increased by 50%. Conclusions. In the face of limited resources and changing reimbursement policies, dialysis providers will need to find ways of reducing costs without compromising the quality of care. Clinical practice guidelines such as KDOQI can be used to assist providers in meeting this challenge. Among Medicare patients who have anemia of chronic kidney disease, adherence to KDOQI treatment recommendations could translate into a significant savings for Medicare. Our findings provide incentive for payers and dialysis centers to examine their current practices and improve the quality and efficiency of anemia treatment in this population

Decades of research in the area of developmental psychobiology have shown that early life experience alters behavioral and brain development, which canalizes development to suit different environments. Recent methodological advances have begun to identify the mechanisms by which early life experiences cause these diverse adult outcomes. Here we present four different research programs that demonstrate the intricacies of early environmental influences on behavioral and brain development in both pathological and normal development. First, an animal model of schizophrenia is presented that suggests prenatal immune stimulation influences the postpubertal emergence of psychosis-related behavior in mice. Second, we describe a research program on infant rats that demonstrates how early odor learning has unique characteristics due to the unique functioning of the infant limbic system. Third, we present work on the rodent Octodon degus, which shows that early paternal and/or maternal deprivation alters development of limbic system synaptic density that corresponds to heightened emotionality. Fourth, a juvenile model of stress is presented that suggests this developmental period is important in determining adulthood emotional well being. The approach of each research program is strikingly different, yet all succeed in delineating a specific aspect of early development and its effects on infant and adult outcome that expands our understanding of the developmental impact of infant experiences on emotional and limbic system development. Together, these research programs suggest that the developing organism's developmental trajectory is influenced by environmental factors beginning in the fetus and extending through adolescence, although the specific timing and nature of the environmental influence has unique impact on adult mental health

Animal studies have shown that in vivo estimates of microvessel density in the brain may be obtained from an MRI-measurable index (Q) provided that a sufficiently high dose of an intravascular paramagnetic contrast agent is employed. Q is determined from the shifts in the transverse relaxation rates induced by the contrast agent, and a high dose is required for the validity of analytic expressions relating Q to the microvessel density. However, the steady-state imaging techniques used in these prior investigations are not appropriate for humans, as the required contrast agent dose is too large. Here results of a pilot study with three subjects are reported. The results suggest that reliable Q measurements can be performed in the human brain at 1.5 T by using an interleaved spin-echo (SE)/gradient-echo (GE) echo-planar imaging (EPI) sequence and a bolus injection of a triple dose of Gd-DTPA. Lower- and upper-bound estimates for the microvessel density were derived from the Q-values, and were found to be in reasonable accord with previously cited values determined by histology

Abstract Immunotherapy holds great promise for Alzheimer's disease (AD) and other conformational disorders but certain adverse reactions need to be overcome. The meningoencephalitis observed in the first AD vaccination trial was likely related to excessive cell-mediated immunity caused by the immunogen, amyloid-beta (Abeta) 1-42, and the adjuvant, QS-21. To avoid this toxicity, we have been using Abeta derivatives in alum adjuvant that promotes humoral immunity. Other potential side effects of immunotherapy are increased vascular amyloid and associated microhemorrhages that may be related to rapid clearance of parenchymal amyloid. Here, we determined if our immunization strategy was associated with this form of toxicity, and if the therapeutic effect was age-dependent. Tg2576 mice and wild-type littermates were immunized from 11 or 19 months and their behaviour evaluated prior to killing at 24 months. Subsequently, plaque- and vascular-Abeta burden, Abeta levels and associated pathology was assessed. The therapy started at the cusp of amyloidosis reduced cortical Abeta deposit burden by 31% and Abeta levels by 30-37%, which was associated with cognitive improvements. In contrast, treatment from 19 months, when pathology is well established, was not immunogenic and therefore did not reduce Abeta burden or improve cognition. Significantly, the immunotherapy in the 11-24 months treatment group, that reduced Abeta burden, did not increase cerebral bleeding or vascular Abeta deposits in contrast to several Abeta antibody studies. These findings indicate that our approach age-dependently improves cognition and reduces Abeta burden when used with an adjuvant suitable for humans, without increasing vascular Abeta deposits or microhemorrhages

Past studies using transgenic models of early-staged amyloid pathology, have suggested that the amyloid pathology progresses in a neurotransmitter-specific manner where cholinergic terminals appear most vulnerable, followed by glutamatergic terminals and finally by somewhat more resistant GABAergic terminals. To determine whether this neurotransmitter-specific progression persists at later pathological stages, presynaptic bouton densities, and the areas of occupation and localization of plaque adjacent dystrophic neurites were quantified in 18-month-old APP(K670N, M671L)+PS1(M146L) doubly transgenic mice. Quantification revealed that transgenic animals had significantly lower cholinergic, glutamatergic and GABAergic presynaptic bouton densities. Cholinergic and glutamatergic dystrophic neurites appear to be heavily influenced by fibrillar Abeta as both types displayed a decreasing area of occupation with respect to increasing plaque size. Furthermore, cholinergic dystrophic neurites reside in closer proximity to plaques than glutamatergic dystrophic neurites, while GABAergic dystrophic neurites were minimal regardless of plaque size. To investigate whether similarities exist in the human AD pathology, a monoclonal antibody (McKA1) against the human vesicular glutamate transporter 1 (VGluT1) was developed. Subsequent staining in AD brain tissue revealed the novel presence of glutamatergic dystrophic neurites, to our knowledge the first evidence of a structural glutamatergic deficit in the AD pathology