Faculty Bibliography

A major problem in the field of neurodegeneration is the basis of selective vulnerability of subsets of neurons to disease. In aging, Alzheimer's disease (AD), and other disorders such as temporal lobe epilepsy, the superficial layers of the entorhinal cortex (EC) are an area of selective vulnerability. In AD, it has been suggested that the degeneration of these neurons may play a role in causing the disease because it occurs at an early stage. Therefore, it is important to define the distinctive characteristics of the EC that make this region particularly vulnerable. It has been shown that neurotrophins such as brain-derived neurotrophic factor (BDNF) are critical to the maintenance of the cortical neurons in the adult brain, and specifically the EC. Here we review the circuitry, distinctive functions, and neurotrophin-dependence of the EC that are relevant to its vulnerability. We also suggest that a protein that is critical to the actions of BDNF, the ARMS/Kidins220 scaffold protein, plays an important role in neurotrophic support of the EC.

Chronic kidney disease (CKD) is an important clinical co-morbidity that increases the risk of death and myocardial infarction in patients with coronary artery disease (CAD) even when treated with guideline-directed therapies. It is unknown, however, whether CKD influences the effects of CAD treatments on patients' health status, their symptoms, function, and quality of life. We performed a post hoc analysis of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) study to compare health status in patients with stable CAD with and without CKD defined as a glomerular filtration rate of <60 ml/min/1.73 m(2) randomized to either percutaneous coronary intervention (PCI) and optimal medical therapy (OMT) or OMT alone. Health status was measured at baseline, 1, 3, 6, 12, 24, and 36 months of follow-up with the Seattle Angina Questionnaire in 310 patients with CKD and 1,719 patients without CKD. Linear mixed-effects models were used to analyze Seattle Angina Questionnaire scores longitudinally. Mean scores for angina-related quality of life, angina frequency, and physical limitation domains improved from baseline values in both patients with and without CKD and plateaued. Early improvement (1 to 6 months) was more common in patients treated with PCI plus OMT than with OMT alone in both patients with and without CKD. Treatment satisfaction scores were high at baseline in all groups and did not change significantly over time. In conclusion, although CKD is an important determinant of event-free survival in patients with stable CAD, it neither precludes satisfactory treatment of angina with PCI plus OMT or OMT alone nor is it associated with an unsatisfactory quality of life.

PURPOSE: To develop an arrhythmia-insensitive rapid (AIR) cardiac T1 mapping pulse sequence for quantification of diffuse fibrosis. METHODS: An arrhythmia-insensitive cardiac T1 mapping pulse sequence was developed based on saturation recovery T1 weighting, which is inherently insensitive to heart rate and rhythm, and two single-shot balanced steady-state free precession image acquisitions with centric k-space ordering, where T1 calculation is inherently insensitive to T2 effects. Its performance against conventional cardiac T1 mapping based on inversion recovery (i.e., MOLLI) is compared. Phantom experiments (T1 ranging from 535 to 2123 ms) were performed with heart rate and rhythm simulated at 60 and 120 beats per minute (bpm) and arrhythmia using an external triggering device. Ten human subjects and 17 large animals were scanned precontrast and 5, 10, and 15 min after contrast agent administration. RESULTS: Compared with the reference T1 mapping, AIR yielded lower normalized root-mean-square error than MOLLI (8% vs. 3%, respectively, at 60 bpm, 28% vs. 3%, respectively, at 120 bpm, and 22% vs. 3%, respectively, at arrhythmia). In vivo studies showed that T1 measurements made by MOLLI and AIR were strongly correlated (r = 0.99) but in poor agreement (mean difference = 161.8 ms, upper and lower 95% limits of agreements = 347.5 ms and -24.0 ms). CONCLUSION: Our AIR pulse sequence may be clinically useful for assessment of diffuse myocardial fibrosis in patients. Magn Reson Med 70:1274-1282, 2013. (c) 2012 Wiley Periodicals, Inc.

Introduction & Objectives: Genetic disorders are among the causes of the most severe stone disease. Among them, primary hyperoxaluria (PH), cystinuria, APRT deficiency, and Dent disease can also be associated with loss of kidney function. Due to their rarity, however, understanding of the impact of these stone diseases on kidney function over time is limited. We performed a cross-sectional study of kidney function in patients with each of these disorders over a range of ages. Material & Methods: Voluntary observational registries of the Rare Kidney Stone Consortium were queried. 155 patients with PH, 53 with cystinuria, 34 with APRT deficiency, and 78 with Dent disease had serum creatinine values available prior to development of end stage kidney failure. Serum creatinine at first presentation was used for calculation of eGFR. Kidney function was calculated by MDRD equation in adults and Schwartz equation in children. Spline curve was used to check linearity of plots. Results were compared with normal eGFR of 116 at 20 years of age with decline of 7.5 ml/min/1.73m2BSA per decade after age 30 years (Lindeman J Am Ger Soc, 1985). Results: Age at eGFR was 16.1+/-17.4, 39.8+/-16.7, 25.9+/-19.1, and 12.4+/-10.0 years (mean+/- SD) and the number of stones at presentation was 4.2+/-10.0, 1.9+/-1.8, 1.7+/-4.8, and 3.1+/-3.9 (mean+/-SD) in PH, cystinuria, APRT deficiency, and Dent patients, respectively. eGFR was 91.5, 80.2, 69.8, and 91.5 ml/min/1.73m2BSA in PH, cystinuria, APRT deficiency, and Dent disease patients, respectively. The change in eGFR per decade was -15 (2.1) ml/min/1.73m2 BSA (SE) in PH, -12 (2.2) in cystinuria, -16 (3.9) in APRT deficiency, and -26 (7.9) in Dent disease. Conclusions: Cross sectional data in patients with PH, cystinuria, APRT deficiency and Dent disease shows more rapid decline in kidney function by decade than observed in healthy subjects. Whether kidney damage is related to stone burden or to other factors remains to be determined. The distinction will be of importanc!

Visual area V2 of the primate cortex receives the largest projection from area V1. V2 is thought to use its striate inputs as the basis for computations that are important for visual form processing, such as signaling angles, object borders, illusory contours, and relative binocular disparity. However, it remains unclear how selectivity for these stimulus properties emerges in V2, in part because the functional properties of the inputs are unknown. We used antidromic electrical stimulation to identify V1 neurons that project directly to V2 (10% of all V1 neurons recorded) and characterized their electrical and visual responses. V2-projecting neurons were concentrated in the superficial and middle layers of striate cortex, consistent with the known anatomy of this cortico-cortical circuit. Most were fast conducting and temporally precise in their electrical responses, and had broad spike waveforms consistent with pyramidal regular-spiking excitatory neurons. Overall, projection neurons were functionally diverse. Most, however, were tuned for orientation and binocular disparity and were strongly suppressed by large stimuli. Projection neurons included those selective and invariant to spatial phase, with roughly equal proportions. Projection neurons found in superficial layers had longer conduction times, broader spike waveforms, and were more responsive to chromatic stimuli; those found in middle layers were more strongly selective for motion direction and binocular disparity. Collectively, these response properties may be well suited for generating complex feature selectivity in and beyond V2.

Aquaporin-4 (AQP4) is the major water channel expressed in the central nervous system (CNS) and is primarily expressed in glial cells. Many studies have shown that AQP4 regulates the response of the CNS to insults or injury, but far less is known about the potential for AQP4 to influence synaptic plasticity or behavior. Recent studies have examined long-term potentiation (LTP), long-term depression (LTD), and behavior in AQP4 knockout (KO) and wild-type mice to gain more insight into its potential role. The results showed a selective effect of AQP4 deletion on LTP of the Schaffer collateral pathway in hippocampus using an LTP induction protocol that simulates pyramidal cell firing during theta oscillations (theta-burst stimulation; TBS). However, LTP produced by a different induction protocol was unaffected. There was also a defect in LTD after low frequency stimulation (LFS) in AQP4 KO mice. Interestingly, some slices from AQP4 KO mice exhibited LTD after TBS instead of LTP, or LTP following LFS instead of LTD. These data suggest that AQP4 and astrocytes influence the polarity of long-term synaptic plasticity (potentiation or depression). These potentially powerful roles expand the influence of AQP4 and astrocytes beyond the original suggestions related to regulation of extracellular potassium and water balance. Remarkably, AQP4 KO mice did not show deficits in basal transmission, suggesting specificity for long-term synaptic plasticity. The mechanism appears to be related to neurotrophins and specifically brain-derived neurotrophic factor (BDNF) because pharmacological blockade of neurotrophin trk receptors or scavenging ligands such as BDNF restored plasticity. The in vitro studies predicted effects in vivo of AQP4 deletion because AQP4 KO mice performed worse using a task that requires memory for the location of objects (object placement). However, performance on other hippocampal-dependent tasks was spared. The results suggest an unanticipated and selective role of AQP4 in synaptic plasticity and spatial memory, and underscore the growing appreciation of the role of glial cells in functions typically attributed to neurons. Implications for epilepsy are discussed because of the previous evidence that AQP4 influences seizures, and the role of synaptic plasticity in epileptogenesis.

In animals, many cells reach their destinations by migrating toward higher concentrations of an attractant. However, the nature, generation, and interpretation of attractant gradients are poorly understood. Using a GFP fusion and a signaling sensor, we analyzed the distribution of the attractant chemokine Sdf1 during migration of the zebrafish posterior lateral line primordium, a cohort of about 200 cells that migrates over a stripe of cells uniformly expressing sdf1. We find that a small fraction of the total Sdf1 pool is available to signal and induces a linear Sdf1-signaling gradient across the primordium. This signaling gradient is initiated at the rear of the primordium, equilibrates across the primordium within 200 min, and operates near steady state. The rear of the primordium generates this gradient through continuous sequestration of Sdf1 protein by the alternate Sdf1-receptor Cxcr7. Modeling shows that this is a physically plausible scenario.

Myelinated nerve fibers have evolved to optimize signal propagation. Each myelin segment is attached to the axon by the unique paranodal axoglial junction (PNJ), a highly complex structure that serves to define axonal ion channel domains and to direct nodal action currents through adjacent nodes. Surprisingly, this junction does not entirely seal the paranodal myelin sheath to the axon and thus does not entirely isolate the perinodal space from the internodal periaxonal space. Rather the paranode is penetrated by extracellular pathways between the myelin sheath and the axolemma for movement of molecules and the flow of current to and from the internodal axon. This review summarizes past and current studies demonstrating these pathways and considers what functional roles they subserve. In addition, modern genetic engineering methods permit modification of individual PNJ constituents, which provides an opportunity to define their specific functions. One component in particular, the transverse bands, plays a key role in maintaining the structure and function of the PNJ. Loss of transverse bands results not in frank demyelination but rather in subtle dysmyelination, which causes significant functional impairment. The consequences of such subtle defects in the PNJ are considered along with the relevance of these studies to human diseases of myelin.