Faculty Bibliography

INTRODUCTION: A case report of a patient with severe lung disease on methadone with chronic hypercapnia. Specific mechanism for chronic hypercapnia is explored with spirometry, ventilation awake and asleep, and CO₂ response. CASE PRESENTATION: A 68 year old man with a history of hypertension, tobacco use, methadone maintenance, presented with chronic hypercapnia (pH 7.43, PCO₂ 55mmHg, CO₂ 30 mmol/L). He had acute dyspnea, cough and wheezing. Chest radiograph was compatible with emphysema. Spirometry confirmed obstructive dysfunction with FEV1 = 0.63 liter (32% predicted) and FEV1/FVC = 32%. Resting ventilation was elevated at 11.7 liter/minute with an elevated dead space fraction (V_D/V_T = 56%). Sleep evaluation revealed multiple central apneic events. He was treated with albuterol and prednisone, and his methadone was discontinued. Thirty-six hours after methadone discontinuation the hypercapnia resolved (pH 7.41, PaCO₂ 37 mmHg, CO₂ 23 mmol/L). Repeat evaluation revealed improved FEV1 = 1.33 liter with severe persistent obstruction (FEV₁/FVC = 45%) and unchanged dead space fraction (V_D/V_T = 53%). A repeat sleep study showed reversal of his central sleep apnea. CO₂ response test revealed a normal ventilation slope. Based on these data, patient was transitioned to Suboxone, a partial opioid mu-receptor agonist with potential for less respiratory suppression. Repeat blood gas remained normal (pH 7.42, PaCO₂ 36, CO₂ 23). DISCUSSION: This case describes the evaluation of a patient with chronic hypercapnia from multiple potential etiologies. Testing revealed obstructive lung disease with increased dead space consistent with COPD. Despite minimal improvement in FEV₁ after therapy, there was no change in the physiologic dead space. Although minute ventilation was elevated during wakefulness, sleep study revealed central apnea compatible with ventilatory depression. Despite the persistence of severe lung disease, the patient was able to achieve eucapnia and remained eucapnic when Suboxone was substituted for Methadone. CONCLUSIONS: Assessment of ventilation both during wakefulness and during sleep uncovered mechanisms for hypoventilation related to methadone use that provided the basis for therapy in a patient with severe lung disease. Understanding the pathophysiology of hypercapnia is required to determine appropriate therapy. Suboxone may be an alternative therapy in patients with chronic hypercapnia

Mutations in MYH7 cause autosomal dominant Laing distal myopathy. We present a family with a previously reported deletion (c.5186_5188delAGA, p.K1729del). Muscle pathology in one family member was characterized by an inflammatory myopathy with rimmed vacuoles, increased MHC Class I expression, and perivascular and endomysial muscle inflammation comprising CD3(+), CD4(+), CD8(+), and CD68(+) inflammatory cells. Interestingly, this biopsy specimen contained TDP-43, p62, and SMI-31-positive protein aggregates typical of inclusion body myositis. These findings should alert physicians to the possibility that patients with MYH7 mutations may have muscle biopsies showing pathologic findings similar to inclusion body myositis.

Alzheimer's disease (AD) is the leading cause of dementia worldwide. Late-onset AD (LOAD), is the most common form of Alzheimer's disease, representing about >95% of cases and early-onset AD represents <5% of cases. Several risk factors have been discovered that are associated with AD, with advancing age being the most prominent. Other environmental risk factors include diabetes mellitus, level of physical activity, educational status, hypertension and head injury. The most well known genetic risk factor for LOAD is inheritance of the apolipoprotein (apo) E4 allele. Recently, rare variants of TREM2 have been reported as a significant risk factor for LOAD, comparable to inheritance of apoE4. In this review we will focus on the role(s) of TREM2 in AD as well as in other neurodegenerative disorders.

Background: Impaired NMDA receptor signaling is believed to contribute to schizophrenia and other psychiatric disorders. NMDA receptors are critical for neural development as well as learning, memory, and cognitive processes in adults. Thus disruption of NMDA receptor activation and synaptic transmission might lead to schizophrenia. Drugs that act as NMDA receptor antagonists (e.g., ketamine) lead to schizophrenic-like symptoms, and human genetic studies have highlighted de novo mutations in NMDA receptors and associated proteins in humans with schizophrenia. However, little is known about how NMDA receptor activation is directly involved in cognitive processes such as perception and memory. Here I will present new work in mouse models showing the connections between a gene implicated in schizophrenia (CNTNAP2), NMDA receptor activation, and control of local circuit dynamics by synaptic plasticity and regulation of excitatory-inhibitory balance in mouse sensory cortex. Methods: We performed electrophysiological experiments in brain slices and in vivo. Some behavioral experiments to examine perception and seizures were also performed. For in vitro experiments, brain slices of wild-type and Cntnap2 mutant animals were made. Synaptic transmission (strength of inhibition relative to strength of excitation) and long-term synaptic plasticity (pairing pre- and postsynaptic spikes to examine spike-timing-dependent plasticity) were assessed with whole-cell current-clamp and voltage-clamp recordings. Methods are similar to our past studies in brain slices (Froemke et al., Nature 2005; Southwell et al., Science 2010). For in vivo experiments, animals were anesthetized and head-fixed, and whole-cell recordings made in auditory or visual cortex. Sensory stimuli (pure tones/vocalizations or light flashes/ sequences, respectively) were presented to the animals; response strength and short- and long-term plasticity were measured. Methods are similar to our past studies in vivo (Froemke et al., Nature 2007; Froemke et al., Nature Neurosci 2013). Results: In Cntnap2 mutant animals, we found that: 1) NMDA receptor amplitude was decreased relative to AMPA receptor transmission, 2) long-term synaptic plasticity was impaired, 3) GABAergic inhibition was imbalanced and uncorrelated to excitation, and 4) sensory responses were unreliable and more variable than in wild-type animals. Each of these latter results (#2-4) might come as a direct consequence of impaired NMDA receptor activation (#1). However, treatment with D-serine could selectively rescue and boost NMDA receptor currents in Cntnap2 mutant mice, suggesting that glycine site modulation could improve synaptic and local circuit function in these animals. Conclusions: Many of the disruptions in Cntnap2 mutant mice (serving as a genetic model of schizophrenia) could have as a root cause reductions in current flux through NMDA receptors. However, glycine site agonists may provide a reasonable therapeutic approach for enhancing NMDA receptor function and improving cognitive processes, especially in the context of trainingbased approaches to recruit mechanisms of longterm synaptic plasticity and rebalancing inhibition with excitation

The signature sequence amplification method (SSAM) described herein is an approach for amplifying noncoding RNA (ncRNA), microRNA (miRNA), and small polynucleotide sequences. A key point of the SSAM technology is the generation of signature sequences. The signature sequences include target sequences (miRNA, ncRNA, and/or any small polynucleotide sequence) flanked by two DNA fragments. Target sequences can be amplified through DNA synthesis, RNA synthesis, or the combination of DNA and RNA synthesis. The amplification of signature sequences provides an efficient and reproducible mechanism to determine the presence or absence of the target miRNAs/ncRNAs, to analyze the quantities of the miRNAs in biological samples, and for miRNA/ncRNA profiling.

Abnormality in the "fear circuitry" has been known as a major neural characteristic of posttraumatic stress disorder (PTSD). Recent studies also revealed decreased functional connectivity in the default mode network in PTSD. The present study aims to investigate, in war-zone-related PTSD, the spontaneous activity and functional connectivity of the amygdala and the precuneus, which are two representative brain regions of the two networks, respectively. Two groups of 52 male US Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF) veterans (PTSD vs. controls), well matched on age and ethnicity, were clinically assessed and then studied in a resting state functional magnetic resonance imaging (fMRI) procedure. Functional connectivity analysis was conducted on the resting state fMRI data with the amygdala and precuneus as seeds. Compared with controls, veterans with PTSD had lower functional connectivity in the default mode network, as well as lower amygdala-frontal functional connectivity. Both the PTSD and the control group had a significant positive precuneal-amygdala functional connectivity without a significant group difference. The magnitudes of spontaneous activity of the amygdala and the precuneus were negatively correlated in the PTSD group and showed significant quadratic relationships with the amount of emotional abuse in early life trauma. These findings may improve our understanding about the relationships between fear circuitry and the default mode network in the context of war-zone-related PTSD.

Antibodies or their derivatives as imaging probes for pathological tau protein have great potential, but have not been well studied. In particular, smaller, single-chain-variable antibody fragments (scFv's) are attractive for detecting tau lesions in live subjects. Here, we generated libraries of scFv's and identified numerous phospho-tau-selective scFv's. Peripheral injection of one of these scFv's consistently resulted in a strong in vivo brain signal in transgenic tauopathy mice, but not in wild-type or amyloid-beta plaque mice. The parent tau antibody provided similar results, albeit with a weaker signal intensity. The imaging signal correlated very well with colocalization of the probe with intraneuronal tau aggregates. Both were associated with markers of endosomes, autophagosomes, and lysosomes, suggesting their interaction in these degradation pathways. Such specific antibody-derived imaging probes have great potential as diagnostic markers for Alzheimer's disease and related tauopathies.