Faculty Bibliography

BACKGROUND: Diffusion tensor imaging studies have shown atypical fractional anisotropy (FA) in individuals with attention-deficit/hyperactivity disorder (ADHD), albeit with conflicting results. We performed meta-analyses of whole-brain voxel-based analyses (WBVBA) and tract-based spatial statistics (TBSS) studies in ADHD, along with a qualitative review of TBSS studies addressing the issue of head motion, which may bias results. METHODS: We conducted a systematic literature search (last search on April 1st, 2016) to identify studies comparing FA values between individuals with ADHD and typically developing (TD) participants. Signed differential mapping was used to compute effect sizes and integrate WBVBA and TBSS studies, respectively. TBSS datasets reporting no between-group motion differences were identified. RESULTS: We identified 14 WBVBA (ADHDn = 314, TDn = 278) and 13 TBSS datasets (ADHDn = 557, TDn = 568). WBVBA meta-analysis showed both significantly lower and higher FA values in individuals with ADHD; TBSS meta-analysis showed significantly lower FA in ADHD compared with TD in four clusters: two in the corpus callosum (isthmus and posterior midbody), one in right inferior fronto-occipital fasciculus, and one in left inferior longitudinal fasciculus. However, four of six datasets confirming no group-differences in motion showed no significant between-group FA differences. CONCLUSIONS: A growing diffusion tensor imaging (DTI) literature (total N = 1,717) and a plethora of apparent findings suggest atypical interhemispheric connection in ADHD. However, FA results in ADHD should be considered with caution, since many studies did not examine potential group differences in head motion, and most of the studies reporting no difference in motion showed no significant results. Future studies should address head motion as a priority and assure that groups do not differ in head motion.

OBJECTIVE:Blunted tachycardia during hypotension is a characteristic feature of patients with autonomic failure, but the range has not been defined. This study reports the range of orthostatic heart rate (HR) changes in patients with autonomic failure caused by neurodegenerative synucleinopathies. METHODS:Patients evaluated at sites of the U.S. Autonomic Consortium (NCT01799915) underwent standardized autonomic function tests and full neurological evaluation. RESULTS:We identified 402 patients with orthostatic hypotension (OH) who had normal sinus rhythm. Of these, 378 had impaired sympathetic activation, i.e., neurogenic OH, and based on their neurological examination were diagnosed with Parkinson disease, dementia with Lewy bodies, pure autonomic failure or multiple system atrophy. The remaining 24 patients had preserved sympathetic activation and their OH was classified as non-neurogenic, due to volume depletion, anemia or polypharmacy. Patients with neurogenic OH had twice the fall in systolic blood pressure (SBP) [-44±25 vs. -21±14 mmHg (mean±SD), p<0.0001] but only one third of the increase in HR than those with non-neurogenic OH (8±8 vs. 25±11 bpm, p<0.0001). A ΔHR/ΔSBP ratio of 0.492 bpm/mmHg had excellent sensitivity (91.3%) and specificity (88.4%) to distinguish between patients with neurogenic vs. non-neurogenic OH (AUC=0.96, p<0.0001). Within patients with neurogenic OH, HR increased more in those with multiple system atrophy (p=0.0003), but there was considerable overlap with patients with Lewy body disorders. INTERPRETATION/CONCLUSIONS:A blunted HR increase during hypotension suggests a neurogenic cause. A ΔHR/ΔSBP ratio lower than 0.5 bpm/mmHg is diagnostic of neurogenic OH.

Objective/UNASSIGNED:Limited attention has been given to ocular injuries associated with traumatic brain injury (TBI). The retina is an extension of the central nervous system and evaluation of ocular damage may offer a less-invasive approach to gauge TBI severity and response to treatment. We aim to characterize acute changes in the mouse eye after exposure to two different models of TBI to assess the utility of eye damage as a surrogate to brain injury. Methods/UNASSIGNED:A model of blast TBI (bTBI) using a shock tube was compared to a lateral fluid percussion injury model (LFPI) using fluid pressure applied directly to the brain. Whole eyes were collected from mice 3 days post LFPI and 24 days post bTBI and were evaluated histologically using a hematoxylin and eosin stain. Results/UNASSIGNED:bTBI mice showed evidence of vitreous detachment in the posterior chamber in addition to vitreous hemorrhage with inflammatory cells. Subretinal hemorrhage, photoreceptor degeneration, and decreased cellularity in the retinal ganglion cell layer was also seen in bTBI mice. In contrast, eyes of LFPI mice showed evidence of anterior uveitis and subcapsular cataracts. Interpretation/UNASSIGNED:We demonstrated that variations in the type of TBI can result in drastically different phenotypic changes within the eye. As such, molecular and phenotypic changes in the eye following TBI may provide valuable information regarding the mechanism, severity, and ongoing pathophysiology of brain injury. Because vitreous samples are easily obtained, molecular changes within the eye could be utilized as biomarkers of TBI in human patients.

ATP-sensitive K+ (KATP) channels uniquely link cellular energy metabolism to membrane excitability and are expressed in diverse cell types that range from the endocrine pancreas to neurons and smooth, skeletal, and cardiac muscle. A decrease in the surface expression of KATP channels has been linked to various disorders, including dysregulated insulin secretion, abnormal blood pressure, and impaired resistance to cardiac injury. In contrast, up-regulation of KATP channel surface expression may be protective, for example, by mediating the beneficial effect of ischemic preconditioning. Molecular mechanisms that regulate KATP channel trafficking are poorly understood. Here, we used cellular assays with immunofluorescence, surface biotinylation, and patch clamping to demonstrate that Eps15 homology domain-containing protein 2 (EHD2) is a novel positive regulator of KATP channel trafficking to increase surface KATP channel density. EHD2 had no effect on cardiac Na+ channels (Nav1.5). The effect is specific to EHD2 as other members of the EHD family-EHD1, EHD3, and EHD4-had no effect on KATP channel surface expression. EHD2 did not directly affect KATP channel properties as unitary conductance and ATP sensitivity were unchanged. Instead, we observed that the mechanism by which EHD2 increases surface expression is by stabilizing KATP channel-containing caveolar structures, which results in a reduced rate of endocytosis. EHD2 also regulated KATP channel trafficking in isolated cardiomyocytes, which validated the physiologic relevance of these observations. Pathophysiologically, EHD2 may be cardioprotective as a dominant-negative EHD2 mutant sensitized cardiomyocytes to ischemic damage. Our findings highlight EHD2 as a potential pharmacologic target in the treatment of diseases with KATP channel trafficking defects.-Yang, H. Q., Jana, K., Rindler, M. J., Coetzee, W. A. The trafficking protein, EHD2, positively regulates cardiac sarcolemmal KATP channel surface expression: role in cardioprotection.

PURPOSE/OBJECTIVE:Treatment of a first-time renal stone consists of acute management followed by medical efforts to prevent stone recurrence. Although nephrolithiasis is roughly 50% heritable, the presence of a family history usually does not affect treatment since most stone disease is regarded as polygenic, ie not attributable to a single gene. Recent evidence has suggested that single mutations could be responsible for a larger proportion of renal stones than previously thought. This intriguing possibility holds the potential to change the management paradigm in stone prevention from metabolically directed therapy to more specific approaches informed by genetic screening and testing. This review synthesizes new findings concerning monogenic kidney stone disease, and provides a concise and clinically useful reference for monogenic causes. It is expected that increased awareness of these etiologies will lead to increased use of genetic testing in recurrent stone formers and further research into the prevalence of monogenic stone disease. MATERIALS AND METHODS/METHODS:We assembled a complete list of genes known to cause or influence nephrolithiasis based on recent reviews and commentaries. We then comprehensively searched PubMed® and Google Scholar™ for all research on each gene having a pertinent role in nephrolithiasis. We determined which genes could be considered monogenic causes of nephrolithiasis. One gene, ALPL, was excluded since nephrolithiasis is a relatively minor aspect of the disorder associated with the gene (hypophosphatasia). We summarized selected studies and assembled clinically relevant details. RESULTS:A total of 27 genes were reviewed in terms of recent findings, mode of inheritance of stone disease, known or supposed prevalence of mutations in the general population of stone patients and specific therapies or considerations. CONCLUSIONS:There is a distinct opportunity for increased use of genetic testing to improve the lives of pediatric and adult stone patients. Several genes first reported in association with rare disease may be loci for novel mutations, heterozygous disease and forme frustes as causes of stones in the broader population. Cases of idiopathic nephrolithiasis should be considered as potentially having a monogenic basis.

PURPOSE: Previous work with body-size objects suggested that loops are optimal MR detectors at low fields, whereas electric dipoles are required to maximize signal-to-noise ratio (SNR) at ultrahigh fields ( >/= 7 T). Here we investigated how many loops and/or dipoles are needed to approach the ultimate intrinsic SNR (UISNR) at various field strengths. METHODS: We calculated the UISNR inside dielectric cylinders mimicking different anatomical regions. We assessed the performance of various arrays with respect to the UISNR. We validated our results by comparing simulated and experimental coil performance maps. RESULTS: Arrays with an increasing number of loops can rapidly approach the UISNR at fields up to 3 T, but are suboptimal at ultrahigh fields for body-size objects. The opposite is true for dipole arrays. At 7 T and above, 16 dipoles provide considerably larger central SNR than any possible loop array, and minimal g factor penalty for parallel imaging. CONCLUSIONS: Electric dipoles can be advantageous at ultrahigh fields because they can produce both curl-free and divergence-free currents, whereas loops are limited to divergence-free contributions only. Combining loops and dipoles may be optimal for body imaging at 3 T, whereas arrays of loops or dipoles alone may perform better at lower or higher field strengths, respectively. Magn Reson Med, 2017. (c) 2017 International Society for Magnetic Resonance in Medicine.

PURPOSE: To describe a new bench measurement based on quality (Q) factors to estimate the coil noise relative to the sample noise of dipole antennas at 7 T. METHODS: Placing a dipole antenna close to a highly conductive sample surrogate (HCSS) greatly reduces radiation loss, and using QHCSS gives a more accurate estimate of coil resistance than Qunloaded . Instead of using the ratio of unloaded and sample-loaded Q factors, the ratio of HCSS-loaded and sample-loaded Q factors should be used at ultra-high fields. A series of simulations were carried out to analyze the power budget of sample-loaded or HCSS-loaded dipole antennas. Two prototype dipole antennas were also constructed for bench measurements to validate the simulations. RESULTS: Simulations showed that radiation loss was suppressed when the dipole antenna was HCSS-loaded, and coil loss was largely the same as when the dipole was loaded by the sample. Bench measurements also showed good alignment with simulations. CONCLUSIONS: Using the ratio QHCSS /Qloaded gives a good estimate of the coil loss for dipole antennas at 7 T, and provides a convenient bench measurement to predict the body noise dominance of dipole antenna designs. The new approach also applies to conventional surface loop coils at ultra-high fields. Magn Reson Med 2017. (c) 2017 International Society for Magnetic Resonance in Medicine.