Faculty Bibliography

The unique vulnerability of the olfactory system to Alzheimer's disease (AD) provides a quintessential translational tool for understanding mechanisms of synaptic dysfunction and pathological progression in the disease. Using the Tg2576 mouse model of beta-amyloidosis, we show that aberrant, hyperactive olfactory network activity begins early in life, before detectable behavioral impairments or comparable hippocampal dysfunction and at a time when amyloid-beta (Abeta) deposition is restricted to the olfactory bulb (OB). Hyperactive odor-evoked activity in the piriform cortex (PCX) and increased OB-PCX functional connectivity emerged at a time coinciding with olfactory behavior impairments. This hyperactive activity persisted until later in life when the network converted to a hyporesponsive state. This conversion was Abeta-dependent, because liver-X receptor agonist treatment to promote Abeta degradation rescued the hyporesponsive state and olfactory behavior. These data lend evidence to a novel working model of olfactory dysfunction in AD and, complimentary to other recent works, suggest that disease-relevant network dysfunction is highly dynamic and region specific, yet with lasting effects on cognition and behavior

Familial dysautonomia (FD) is caused by an intronic splice mutation in the IKBKAP gene that leads to partial skipping of exon 20 and tissue-specific reduction in I-kappa-B kinase complex-associated protein/elongation protein 1 (IKAP/ELP-1) expression. Kinetin (6-furfurylaminopurine) has been shown to improve splicing and increase WT IKBKAP mRNA and IKAP protein expression in FD cell lines and carriers. To determine whether oral kinetin treatment could alter mRNA splicing in FD subjects and was tolerable, we administered kinetin to eight FD individuals homozygous for the splice mutation. Subjects received 23.5 mg/Kg/d for 28 d. An increase in WT IKBKAP mRNA expression in leukocytes was noted after 8 d in six of eight individuals; after 28 d, the mean increase compared with baseline was significant (p = 0.002). We have demonstrated that kinetin is tolerable in this medically fragile population. Not only did kinetin produce the desired effect on splicing in FD patients but also that effect seems to improve with time despite lack of dose change. This is the first report of a drug that produces in vivo mRNA splicing changes in individuals with FD and supports future long-term trials to determine whether kinetin will prove therapeutic in FD patients. ABBREVIATIONS::

Purpose: To test the hypothesis that anterior cingulate cortex (ACC) subregions in patients with schizophrenia are metabolically different from those in healthy control subjects. Materials and Methods: This institutional review board-approved study was HIPAA compliant, and all participants provided written informed consent. Twenty-two patients with schizophrenia (13 male, nine female; 39.4 years +/- 10.6 [standard deviation]) and 11 age- and sex-matched control subjects (seven male, four female; 35.5 years +/- 10.7) underwent magnetic resonance (MR) imaging and three-dimensional 3-T voxel proton MR spectroscopy to measure absolute rostral and caudal ACC N-acetylaspartate (NAA), creatine (Cr), and choline (Cho) concentrations. Exact Mann-Whitney test was used to compare patient data with control data, paired-sample Wilcoxon signed rank test was used to compare subregions within groups, and receiver operating characteristic curve analysis was used to assess sensitivity and specificity in diagnosis of schizophrenia. Results: There were no significant metabolic differences between patients and control subjects or between ACC subregions in control subjects. In patients, rostral ACC NAA and Cr concentrations were significantly lower than those in caudal ACC (6.2 mM +/- 1.3 vs 7.1 mM +/- 1.3, P < .01; 5.7 mmol/L +/- 1.4 vs 6.3 mmol/L +/- 1.6, P < .01; respectively); however, this did not hold true for Cho concentrations (1.7 mmol/L +/- 0.5 vs 1.8 mmol/L +/- 0.5). For individual differences between caudal and rostral measurements, only NAA in patients was different from that in control subjects (0.9 mmol/L +/- 1.3 vs -0.1 mmol/L +/- 0.5, P < .01), enabling prediction of schizophrenia with 68% sensitivity and 91% specificity, for a difference of more than 0.4. Conclusion: Significant differences between caudal and rostral NAA concentration are found in ACC of patients with schizophrenia but not in ACC of healthy control subjects, indicating that neuronal density or integrity differences between ACC subregions may be characteristic of the disease. (c) RSNA, 2011

Nasal expiratory positive airway pressure (nEPAP) delivered with a disposable device (Provent, Ventus Medical) has been shown to improve sleep-disordered breathing (SDB) in some subjects. Possible mechanisms of action are 1) increased functional residual capacity (FRC), producing tracheal traction and reducing upper airway (UA) collapsibility, and 2) passive dilatation of the airway by the expiratory pressure, carrying over into inspiration. Using MRI, we estimated change in FRC and ventilation, as well as UA cross-sectional area (CSA), in awake patients breathing on and off the nEPAP device. Ten patients with SDB underwent nocturnal polysomnography and MRI with and without nEPAP. Simultaneous images of the lung and UA were obtained at 6 images/s. Image sequences were obtained during mouth and nose breathing with and without the nEPAP device. The nEPAP device produced an end-expiratory pressure of 4-17 cmH(2)O. End-tidal Pco(2) rose from 39.7 +/- 5.3 to 47.1 +/- 6.0 Torr (P < 0.01). Lung volume changes were estimated from sagittal MRI of the right lung. Changes in UA CSA were calculated from transverse MRI at the level of the pharynx above the epiglottis. FRC determined by MRI was well correlated to FRC determined by N(2) washout (r = 0.76, P = 0.03). nEPAP resulted in a consistent increase in FRC (46 +/- 29%, P < 0.001) and decrease in ventilation (50 +/- 15%, P < 0.001), with no change in respiratory frequency. UA CSA at end expiration showed a trend to increase. During wakefulness, nEPAP caused significant hyperinflation, consistent with an increase in tracheal traction and a decrease in UA collapsibility. Direct imaging effects on the UA were less consistent, but there was a trend to dilatation. Finally, we showed significant hypoventilation and rise in Pco(2) during use of the nEPAP device during wakefulness and sleep. Thus, at least three mechanisms of action have the potential to contribute to the therapeutic effect of nEPAP on SDB

The vulnerability of the olfactory system to Alzheimer's disease (AD) pathology and the high incidence of olfactory perceptual dysfunction in early stages of the disease makes the olfactory system a unique model for understanding mechanisms of synaptic and neural network dysfunction in AD. Here we demonstrate aberrant neural oscillations within the olfactory bulb (OB) and piriform cortex (PCX) of mice overexpressing human mutations of amyloid precursor protein (APP). Network dysfunction was evident starting at 3 months of age in APP mice, prior to the onset of significant behavioral impairments or comparable hippocampal network dysfunction. Coinciding with the onset of behavioral impairments, we found hyperactivity of odor-evoked responses in the PCX and enhanced coherence between the OB and PCX. In contrast, older APP mice with established disease-related pathology were characterized by hyporesponsive PCX odor-evoked activity and impaired behavior which were both recovered by treatment with a Liver-X Receptor (LXR) agonist. These results complement recent findings in other neural networks and suggest that disease-relevant network dysfunction can be transient and region specific, yet with lasting effects on cognition and behavior

The central nervous system is plastic throughout life, but is most sensitive to the statistics of the sensory environment during critical periods of early postnatal development. In the auditory cortex, various forms of acoustic experience have been found to shape the formation of receptive fields and influence the overall rate of cortical organization. The synaptic mechanisms that control cortical receptive field plasticity are beginning to be described, particularly for frequency tuning in rodent primary auditory cortex. Inhibitory circuitry plays a major role in critical period regulation, and new evidence suggests that the formation of excitatory-inhibitory balance determines the duration of critical period plasticity for auditory cortical frequency tuning. Cortical inhibition is poorly tuned in the infant brain, but becomes co-tuned with excitation in an experience-dependent manner over the first postnatal month. We discuss evidence suggesting that this may be a general feature of the developing cortex, and describe the functional implications of such transient excitatory-inhibitory imbalance

This study was designed to understand molecular and cellular mechanisms underlying aggressive behaviors in mice exposed to repeated interactions in their homecage with conspecifics. A resident-intruder procedure was employed whereby two males were allowed to interact for 10 min trials, and aggressive and/or submissive behaviors (e.g., degree of attacking, biting, chasing, grooming, rearing, or upright posture) were assessed. Following 10 days of behavioral trials, brains were removed and dissected into specific regions including the cerebellum, frontal cortex, hippocampus, midbrain, pons, and striatum. Gene expression analysis was performed using real-time quantitative polymerase-chain reaction (qPCR) for catechol-O-methyltransferase (COMT) and tyrosine hydroxylase (TH). Compared to naive control mice, significant up regulation of COMT expression of residents was observed in the cerebellum, frontal cortex, hippocampus, midbrain, and striatum; in all of these brain regions the COMT expression of residents was also significantly higher than that of intruders. The intruders also had a significant down regulation (compared to naive control mice) within the hippocampus, indicating a selective decrease in COMT expression in the hippocampus of submissive subjects. Immunoblot analysis confirmed COMT up regulation in the midbrain and hippocampus of residents and down regulation in intruders. qPCR analysis of TH expression indicated significant up regulation in the midbrain of residents and concomitant down regulation in intruders. These findings implicate regionally- and behaviorally-specific regulation of COMT and TH expression in aggressive and submissive behaviors. Additional molecular and cellular characterization of COMT, TH, and other potential targets is warranted within this animal model of aggression

A chromosome 22q13 locus strongly associates with increased risk for idiopathic focal segmental glomerulosclerosis (FSGS), HIV-1-associated nephropathy (HIVAN), and hypertensive ESRD among individuals of African descent. Although initial studies implicated MYH9, more recent analyses localized the strongest association within the neighboring APOL1 gene. In this replication study, we examined the six top-most associated variants in APOL1 and MYH9 in an independent cohort of African Americans with various nephropathies (44 with FSGS, 21 with HIVAN, 32 with IgA nephropathy, and 74 healthy controls). All six variants associated with FSGS and HIVAN (additive ORs, 1.8 to 3.0; P values 3 x 10(-2) to 5 x 10(-5)) but not with IgA nephropathy. In conditional and haplotype analyses, two APOL1 haplotypes accounted for virtually all of the association with FSGS and HIVAN on chromosome 22q13 (haplotype P value = 5.6 x 10(-8)). To assess the role of MYH9 deficiency in nephropathy, we crossbred Myh9-haploinsufficient mice (Myh9(+/-)) with HIV-1 transgenic mice. Myh9(+/-) mice were healthy and did not demonstrate overt proteinuria or nephropathy, irrespective of the presence of the HIV-1 transgene. These data further support the strong association of genetic variants in APOL1 with susceptibility to FSGS and HIVAN among African Americans.

Abstract Background and Purpose: Oxalobacter formigenes (OF) may play a protective role in preventing calcium oxalate stones. This is the first prospective study to evaluate the effect of antibiotics on OF colonization. Intestinal colonization by OF is associated with reduced urinary oxalate excretion. Exposure to antibiotics may be an important factor determining rates of colonization. Materials and Methods: The effect of antibiotics on OF colonization was compared in two groups: A group receiving antibiotics for gastric infection with Helicobacter pylori (HP) and a group without HP whose members were not receiving antibiotics. OF colonization in stool was detected by oxalate degradation at baseline and after 1 and 6 months. Results: The prevalence at baseline of intestinal colonization with OF was 43.1% among all patients screened. Among the 12 patients who were positive for OF who did not receive antibiotics, 11 (92%) had OF on stool tests at 1 month and 6 months. Of the 19 participants who were positive for OF and who received antibiotics for HP, only 7 (36.8%) continued to be colonized by OF on follow-up stool testing at 1 and 6 months (P=0.003 by Fisher exact test). Amoxicillin and clarithromycin caused 62.5% of subjects to become negative for OF at 1 month; 56.2% remained negative for OF at 6 months. Conclusions: Antibiotics for HP infection effectively reduced colonization with OF, an effect present at 1 and 6 months after treatment. The lasting elimination of OF could be associated with hyperoxaluria and be a factor in recurrent kidney stone disease

Pathological tau protein is found in Alzheimer's disease and related tauopathies. The protein is hyperphosphorylated and/or mutated which leads to aggregation and neurotoxicity. Because cognitive functions correlate well with the degree of tau pathology, clearing these aggregates is a promising therapeutic approach. Studies pioneered by our laboratory and confirmed by others have shown that both active and passive immunizations targeting disease-related tau epitopes successfully reduce tau aggregates in vivo and slow or prevent behavioral impairments in mouse models of tauopathy. Here, we summarize recent advances in this new field