The NAAG'ing Concerns of Modeling Human Alzheimer's Disease in Mice.

Studies over the past two decades report significant reductions in brain N-acetylaspartyl glutamate (NAAG) levels in neurodegenerative diseases with associated cognitive impairment, including Alzheimer's disease (AD). Because NAAG is cleaved by glutamate carboxypeptidase II (GCPII), restoration of brain NAAG levels via GCPII inhibition is a potential therapeutic strategy for AD. Herein, studies were conducted to identify an appropriate murine model of AD that recapitulates human brain NAAG changes in order to preclinically evaluate the therapeutic benefit of GCPII inhibition. Our opposing findings of brain NAAG changes in human and mouse AD highlights the limited predictive value of AD mouse models.

Effects of Sleep, Physical Activity, and Shift Work on Daily Mood: a Prospective Mobile Monitoring Study of Medical Interns.

BACKGROUND: Although short sleep, shift work, and physical inactivity are endemic to residency, a lack of objective, real-time information has limited our understanding of how these problems impact physician mental health. OBJECTIVE: To understand how the residency experience affects sleep, physical activity, and mood, and to understand the directional relationships among these variables. DESIGN: A prospective longitudinal study. SUBJECTS: Thirty-three first-year residents (interns) provided data from 2 months pre-internship through the first 6 months of internship. MAIN MEASURES: Objective real-time assessment of daily sleep and physical activity was assessed through accelerometry-based wearable devices. Mood scaled from 1 to 10 was recorded daily using SMS technology. Average compliance rates prior to internship for mood, sleep, and physical activity were 77.4, 80.2, and 93.7%, and were 78.8, 53.0, and 79.9% during internship. KEY RESULTS: After beginning residency, interns lost an average of 2 h and 48 min of sleep per week (t = - 3.04, p < .01). Mood and physical activity decreased by 7.5% (t = - 3.67, p < .01) and 11.5% (t = - 3.15, p < .01), respectively. A bidirectional relationship emerged between sleep and mood during internship wherein short sleep augured worse mood the next day (b = .12, p < .001), which, in turn, presaged shorter sleep the next night (b = .06, p = .03). Importantly, the effect of short sleep on mood was twice as large as mood's effect on sleep. Lastly, substantial shifts in sleep timing during internship (sleeping ≥ 3 h earlier or later than pre-internship patterns) led to shorter sleep (earlier: b = - .36, p < .01; later: b = - 1.75, p < .001) and poorer mood (earlier: b = - .41, p < .001; later: b = - .41, p < .001). CONCLUSIONS: Shift work, short sleep, and physical inactivity confer a challenging environment for physician mental health. Efforts to increase sleep opportunity through designing shift schedules to allow for adequate opportunity to resynchronize the circadian system and improving exercise compatibility of the work environment may improve mood in this depression-vulnerable population.

Defense Automated Neurobehavioral Assessment Accurately Measures Cognition in Patients Undergoing Electroconvulsive Therapy for Major Depressive Disorder.

OBJECTIVES: The Defense Automated Neurobehavioral Assessment (DANA) is an electronic cognitive test battery. The present study compares DANA to the standard Mini-Mental State Examination (MMSE) in subjects undergoing electroconvulsive therapy for the treatment of major depressive disorder. METHODS: Seventeen inpatient subjects in the Johns Hopkins Hospital Department of Psychiatry were administered longitudinal paired DANA and MMSE tests (7.6 ± 4.1 per patient) from January 10, 2014 to September 26, 2014. Regression analyses were conducted (with or without MMSE scores of 30) to study the impact of the MMSE upper limit, and within-subject regression analyses were conducted to compare MMSE and DANA scores over time. RESULTS: Statistically significant relationships were measured between DANA and MMSE scores. Relationships strengthened when MMSE scores of 30 were omitted from analyses, demonstrating a ceiling effect of the MMSE. Within-subject analyses revealed relationships between MMSE and DANA scores over the duration of the inpatient stay. CONCLUSIONS: Defense Automated Neurobehavioral Assessment is an electronic, mobile, repeatable, sensitive, and valid method of measuring cognition over time in depressed patients undergoing electroconvulsive therapy treatment. Automation of the DANA allows for more frequent cognitive testing in a busy clinical setting and enhances cognitive assessment sensitivity with a timed component to each test.

Exploring the Mechanism of the Clinical Encounter on Depressive Symptoms in Young Adults: A Path Analysis.

Elucidating mechanisms of how high quality clinical encounters with providers may alleviate depressive symptoms in young adults are critical to reduce psychological morbidity and disability. Guided by Street's Model of Health Communication (SMHC), this study explores the predictive relationships of the clinical encounter, which includes communication functions (patient-provider communication and patient self-appraisal of communication skills with provider) and proximal outcomes (patient activation; PA) to improve health outcomes (depressive symptoms) in young adults. This study of young adults (n = 60) employed path analysis to examine the overall model fit and direct and indirect effects of each variable on depressive symptoms. The final SMHC had excellent model fit (X2 = 2.26, p =.32, TLI =.99, CFI = 1.00, RMSEA =.05). Patient-provider communication and self-appraised communication skills with providers had indirect effects on depressive symptoms and a direct effect on PA; PA had a direct effect on depressive symptoms (R2 =.30, p <.01). Findings elucidate potential novel targets, amenable to behavioral intervention, to improve depressive symptoms within the clinical encounter, and provide a foundation for hypothesis-driven model testing among young adults with depressive symptoms.

Dose-dependent inhibition of GCPII to prevent and treat cognitive impairment in the EAE model of multiple sclerosis.

There are no treatments for cognitive impairment in multiple sclerosis (MS). Novel treatments can be evaluated in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS that displays both physical and cognitive impairments. Inhibition of the neuropeptidase glutamate carboxypeptidase II (GCPII) has previously been shown to ameliorate cognitive impairment in EAE, but dosing has not yet been optimized and only a prevention treatment paradigm has been explored. In the study described herein, the dose response of the GCPII inhibitor 2-(phosphonomethyl)pentanedioic acid (2-PMPA) was evaluated for preventing cognitive impairment in EAE mice. Mice were immunized and received daily injections of vehicle or 2-PMPA (10, 30, 100, or 300 mg/kg) from the time of immunization (i.e. day 0). Although no doses of the drug altered physical disease severity, the 100mg/kg dose was most efficacious at preventing cognitive impairments in Barnes maze performance. Dose-related increases in brain NAAG levels were observed in post-mortem analysis, confirming target engagement. Using the 100mg/kg dose, we subsequently evaluated 2-PMPA׳s ability to treat EAE-induced symptoms by commencing treatment after the onset of physical signs of EAE (i.e. day 14). Mice were immunized for EAE and received daily injections of vehicle or 100mg/kg 2-PMPA starting two weeks post-immunization. Significant improvements in both cognitive performance and increases in brain NAAG levels were observed. GCPII inhibition is a promising treatment for cognitive impairment in MS, and doses providing equivalent exposures to 100mg/kg 2-PMPA in mice should be evaluated in clinical studies for the prevention and/or treatment of MS-related cognitive impairment.

Separate may not be equal: a preliminary investigation of clinical correlates of electronic psychiatric record accessibility in academic medical centers.

OBJECTIVES: Electronic Medical Records (EMR) have the potential to improve the coordination of healthcare in this country, yet the field of psychiatry has lagged behind other medical disciplines in its adoption of EMR. METHODS: Psychiatrists at 18 of the top US hospitals completed an electronic survey detailing whether their psychiatric records were stored electronically and accessible to non-psychiatric physicians. Electronic hospital records and accessibility statuses were correlated with patient care outcomes obtained from the University Health System Consortium Clinical Database available for 13 of the 18 top US hospitals. RESULTS: 44% of hospitals surveyed maintained most or all of their psychiatric records electronically and 28% made psychiatric records accessible to non-psychiatric physicians; only 22% did both. Compared with hospitals where psychiatric records were not stored electronically, the average 7-day readmission rate of psychiatric patients was significantly lower at hospitals with psychiatric EMR (5.1% vs. 7.0%, p = .040). Similarly, the 14 and 30-day readmission rates at hospitals where psychiatric records were accessible to non-psychiatric physicians were lower than those of their counterparts with non-accessible records (5.8% vs. 9.5%, p = .019, 8.6% vs. 13.6%, p = .013, respectively). The 7, 14, and 30-day readmission rates were significantly lower in hospitals where psychiatric records were both stored electronically and made accessible than at hospitals where records were either not electronic or not accessible (4% vs 6.6%, 5.8% vs 9.1%, 8.9 vs 13%, respectively, all with p = 0.045). CONCLUSIONS: Having psychiatric EMR that were accessible to non-psychiatric physicians correlated with improved clinical care as measured by lower readmission rates specific for psychiatric patients.

Inhibition of glutamate carboxypeptidase II (GCPII) activity as a treatment for cognitive impairment in multiple sclerosis.

Half of all patients with multiple sclerosis (MS) experience cognitive impairment, for which there is no pharmacological treatment. Using magnetic resonance spectroscopy (MRS), we examined metabolic changes in the hippocampi of MS patients, compared the findings to performance on a neurocognitive test battery, and found that N-acetylaspartylglutamate (NAAG) concentration correlated with cognitive functioning. Specifically, MS patients with cognitive impairment had low hippocampal NAAG levels, whereas those with normal cognition demonstrated higher levels. We then evaluated glutamate carboxypeptidase II (GCPII) inhibitors, known to increase brain NAAG levels, on cognition in the experimental autoimmune encephalomyelitis (EAE) model of MS. Whereas GCPII inhibitor administration did not affect physical disabilities, it increased brain NAAG levels and dramatically improved learning and memory test performance compared with vehicle-treated EAE mice. These data suggest that NAAG is a unique biomarker for cognitive function in MS and that inhibition of GCPII might be a unique therapeutic strategy for recovery of cognitive function.

Imaging serotonergic transmission with [11C]DASB-PET in depressed and non-depressed patients infected with HIV.

INTRODUCTION: Site-selective imaging can provide significant insight into the mechanism of HIV-associated neurological disease. The goal of this study was to evaluate the involvement of serotonergic transmission in HIV-associated depression using [(11)C]DASB, a serotonin transporter (5-HTT)-specific radiopharmaceutical for positron emission tomography (PET). METHODS: Nine depressed HIV+ subjects (HIV-D), 9 non-depressed HIV+ subjects (HIV-ND) and 7 healthy controls (HC) underwent an MRI scan and a [(11)C]DASB-PET scan. The outcome measure was 5-HTT binding potential normalized to non-displaceable tissue radioligand (BP(ND)). RESULTS: HIV-ND subjects had lower mean regional 5-HTT BP(ND) estimates across regions compared to HC, while HIV-D subjects demonstrated higher mean regional binding values than HIV-ND subjects in most regions. Prior to correction for the false discovery rate, HIV-ND had significantly lower BP(ND) values compared to HC subjects in two regions (insula and anterior cingulate) and all HIV+ patients had significantly lower binding than HC in all regions except for the midbrain, thalamus and pons. After correction for the false discovery rate, only the insula showed significantly lower binding in HIV+ subjects compared to HC (P<0.0045). Despite a significant difference in the duration of illness between the HIV-D and HIV-ND groups, there was no definite correlation between the duration of illness and BP(ND). CONCLUSION: Lower [(11)C]DASB binding in HIV+ patients compared to HC may reflect serotonergic neuronal loss as a component of generalized HIV-associated neurodegeneration. Higher mean regional BP(ND) values in HIV-D compared to HIV-ND subjects could reflect increased density of 5-HTT, leading to increased clearance of serotonin from the synapse, which could account, in part, for symptoms of depression. The lack of correlation between duration of illness and binding argues against these findings being the result of differential neurodegeneration only. Our findings suggest a possible role for dysregulated serotonergic transmission in HIV-associated depression.

Quality care in transverse myelitis: a responsive protocol.

This study was conducted to aid in the development of a multidisciplinary care center for patients with transverse myelitis. We surveyed the parents of 20 children diagnosed with transverse myelitis between the ages of 0.5 and 21 years to understand their experiences in navigating the health care system. We analyzed acute care events and long-term follow-up in relation to patient satisfaction. Results showed satisfactory ratings in the vicinity of 50% in key areas such as the articulation of a treatment plan. A significant disparity was found in the patients' desire for specialty care and their ability to procure such care. In all, 90% of patients expressed a desire to consult with a psychiatrist, but only 25% were successful in making a visit, a 64% deficit; 70% of respondents also desired to see a gastroenterologist, with only 25% actually doing so, leaving a 43% gap. Recommendations and patient opinions regarding the creation of a collaborative care environment are noted. Research with a larger sample will further elucidate the needs in transverse myelitis patient care.

Reduction of disease activity and disability with high-dose cyclophosphamide in patients with aggressive multiple sclerosis.

OBJECTIVE: To explore the safety and effectiveness of high-dose cyclophosphamide (HiCy) without bone marrow transplantation in patients with aggressive multiple sclerosis (MS). DESIGN: A 2-year open-label trial of patients with aggressive relapsing-remitting multiple sclerosis (RRMS) given an immunoablative regimen of HiCy (50 mg/kg/d for 4 consecutive days) with no subsequent immunomodulatory therapy unless disease activity reappeared that required rescue therapy. SETTING: The Johns Hopkins University Multiple Sclerosis Center, Baltimore, Maryland. Patients A total of 21 patients with RRMS were screened for eligibility and 9 patients were enrolled in the trial. Patients were required to have 2 or more gadolinium-enhancing lesions on each of 2 pretreatment magnetic resonance imaging scans, at least 1 clinical exacerbation in the 12 months prior to HiCy treatment, or a sustained increase of 1.0 point or higher on the Expanded Disability Status Scale (EDSS) in the preceding year. Intervention Patients received 50 mg/kg/d of cyclophosphamide intravenously for 4 consecutive days, followed by 5 mug/kg/d of granulocyte colony-stimulating factor 6 days after completion of HiCy treatment, until the absolute neutrophil count exceeded 1.0 x 10(9) cells/L for 2 consecutive days. MAIN OUTCOME MEASURES: The primary outcome of the study was the safety and tolerability of HiCy in patients with RRMS. Secondary outcome measures included a change in gadolinium-enhancing lesions on magnetic resonance images and a change in disability measures (EDSS and Multiple Sclerosis Functional Composite). RESULTS: Nine patients were treated and followed up for a mean period of 23 months. Eight patients had failed conventional therapy and 1 was treatment naive. The median age at time of entry was 29 years (range, 20-47 years). All patients developed transient total or near-total pancytopenia as expected, followed by hematopoietic recovery in 10 to 17 days, stimulated by granulocyte colony-stimulating factor. There were no deaths or unexpected serious adverse events. There was a statistically significant reduction in disability (EDSS) at follow-up (mean [SD] decrease, 2.11 [1.97]; 39.4%; P = .02). The mean (SD) number of gadolinium-enhancing lesions on the 2 pretreatment scans were 6.5 (2.1) and 1.2 (2.3) at follow-up (81.4% reduction; P = .01). Two patients required rescue treatment with other immunomodulatory therapies during the study owing to MS exacerbations. CONCLUSION: Treatment with HiCy was safe and well tolerated in our patients with MS. Patients experienced a pronounced reduction in disease activity and disability after HiCy treatment. This immunoablative regimen of cyclophosphamide for patients with aggressive MS is worthy of further study and may be an alternative to bone marrow transplantation. Published online June 9, 2008 (doi:10.1001/archneurol.65.8.noc80042).

Interleukin-17 in transverse myelitis and multiple sclerosis.

CSF IL-6 is elevated in transverse myelitis (TM) and predicts disability. Since IL-17 regulates cytokines (TNFalpha, IL-1beta and IL-6) known to stimulate IL-6 production by astrocytes, we sought to determine whether IL-17 was increased in TM and MS compared to healthy controls (HC) and other neurologic diseases (OND). IL-17 and IL-6 levels were measured in stimulated peripheral blood mononuclear cell (PBMC) supernatants from HC, MS, TM and OND. IL-17 was increased in TM compared to HC, MS, and OND (mean pg/ml+/-standard error; HC: 36.1+/-11.7, MS: 89.4+/-23.3, TM: 302.6+/-152.5, OND: 41.2+/-13.0, p=0.01). IL-6 was increased in TM relative to MS and HC (HC: 2624 pg/ml+/-641, MS: 6129+/-982, TM: 12,536+/-2657, OND: 6920+/-1801, p<0.002). MS patients with early disease (<2 years) also had increased levels of IL-17 (p<0.04) and IL-6 (p<0.05). Cytokine neutralization experiments demonstrated that IL-6 was the main inducer of astrocyte IL-6 production. We conclude that IL-17 and IL-6 production from PBMC in TM and early MS are increased and induce astrocyte IL-6 production through IL-6.

Neuropsychiatric manifestations of depression in multiple sclerosis: neuroinflammatory, neuroendocrine, and neurotrophic mechanisms in the pathogenesis of immune-mediated depression.

Evidence suggests that depression in multiple sclerosis (MS) is largely biologically mediated by some of the same processes involved in the immunopathogenesis of this neurologic disease. In particular, the increase in proinflammatory cytokines, activation of the hypothalamic-pituitary-adrenal (HPA) axis, and reduction in neurotrophic factors that occur in MS may each account for the increased rate of depression seen in MS. The possible contributions of these neuroinflammatory, neuroendocrine, and neurotrophic mechanisms suggest a diverse array of novel treatment strategies for depression, both in the context of inflammatory conditions as well as in idiopathic depression. Furthermore, if such processes in MS play a causative role in the pathogenesis of depression, and depression in turn has affects on neurophysiological processes related to immune function, then treatment of depression might have a positive effect on MS disease progression. This makes treating MS depression a neuropsychiatric imperative.

Demyelinating disorders: update on transverse myelitis.

Transverse myelitis (TM) is a focal inflammatory disorder of the spinal cord. Perivascular monocytic and lymphocytic infiltration, demyelination, and axonal injury are prominent histopathogic features of TM. The clinical manifestations of TM are consequent to dysfunction of motor, sensory, and autonomic pathways. At peak deficit, 50% of patients with TM are completely paraplegic (with no volitional movements of legs), virtually all have some degree of bladder dysfunction, and 80% to 94% have numbness, paresthesias, or band-like dysesthesias. Longitudinal case series of TM reveal that approximately one third of patients recover with little to no sequelae, one third are left with a moderate degree of permanent disability, and one third have severe disability. Recent studies have shown that the cytokine interleukin-6 may be a useful biomarker, as the levels of interleukin-6 in the cerebrospinal fluid of acute TM patients strongly correlate with and are highly predictive of disability. Clinical trials testing the efficacy of promising axonoprotective agents in combination with intravenous steroids in the treatment of TM are currently underway.

IL-6 induces regionally selective spinal cord injury in patients with the neuroinflammatory disorder transverse myelitis.

Transverse myelitis (TM) is an immune-mediated spinal cord disorder associated with inflammation, demyelination, and axonal damage. We investigated the soluble immune derangements present in TM patients and found that IL-6 levels were selectively and dramatically elevated in the cerebrospinal fluid and directly correlated with markers of tissue injury and sustained clinical disability. IL-6 was necessary and sufficient to mediate cellular injury in spinal cord organotypic tissue culture sections through activation of the JAK/STAT pathway, resulting in increased activity of iNOS and poly(ADP-ribose) polymerase (PARP). Rats intrathecally infused with IL-6 developed progressive weakness and spinal cord inflammation, demyelination, and axonal damage, which were blocked by PARP inhibition. Addition of IL-6 to brain organotypic cultures or into the cerebral ventricles of adult rats did not activate the JAK/STAT pathway, which is potentially due to increased expression of soluble IL-6 receptor in the brain relative to the spinal cord that may antagonize IL-6 signaling in this context. The spatially distinct responses to IL-6 may underlie regional vulnerability of different parts of the CNS to inflammatory injury. The elucidation of this pathway identifies specific therapeutic targets in the management of CNS autoimmune conditions.

Recurrent transverse myelitis following neurobrucellosis: immunologic features and beneficial response to immunosuppression.

The authors report the clinical course and immune system response of a patient with disease-associated recurrent transverse myelitis (TM) following cerebral infection with Brucellosis melitensis. The patient suffered four recurrences of his TM (each at a distinct spinal cord level) over the course of 2 years following his initial presentation, which ultimately progressed to quadriplegia. He had progressively declining cerebrospinal fluid (CSF) brucella antibody titers, suggesting a postinfectious, rather than an infectious, etiology. The authors simultaneously examined the expression of multiple cytokines in the CSF of this patient using cytokine antibody arrays and found a marked elevation of interleukin (IL)-6, IL-8, and macrophage chemoattractant protein (MCP)-1 levels relative to controls. Quantitative enzyme-linked immunosorbent assay (ELISA) analysis of the CSF confirmed a 1700-fold elevation of IL-6 and more modest elevations of IL-8 and MCP-1. IL-6 levels returned to baseline following treatment of the patient with intravenous cyclophosphamide and plasma exchange and the patient experienced a significant and sustained recovery of function.

Inositol 1,4,5-trisphosphate receptor/GAPDH complex augments Ca2+ release via locally derived NADH.

NADH regulates the release of calcium from the endoplasmic reticulum by modulation of inositol 1,4,5-trisphosphate receptors (IP3R), accounting for the augmented calcium release of hypoxic cells. We report selective binding of IP3R to GAPDH, whose activity leads to the local generation of NADH to regulate intracellular calcium signaling. This interaction requires cysteines 992 and 995 of IP3R and C150 of GAPDH. Addition of native GAPDH and NAD+ to WT IP3R stimulates calcium release, whereas no stimulation occurs with C992S/995S IP3R that cannot bind GAPDH. Thus, the IP3R/GAPDH interaction likely enables cellular energy dynamics to impact calcium signaling.

Diagnosis and management of acute myelopathies.

BACKGROUND: Acute myelopathies represent a heterogeneous group of disorders with distinct etiologies, clinical and radiologic features, and prognoses. Transverse myelitis (TM) is a prototype member of this group in which an immune-mediated process causes neural injury to the spinal cord, resulting in varying degrees of weakness, sensory alterations, and autonomic dysfunction. TM may exist as part of a multifocal CNS disease (eg, MS), multisystemic disease (eg, systemic lupus erythematosus), or as an isolated, idiopathic entity. REVIEW SUMMARY: In this article, we summarize recent classification and diagnostic schemes, which provide a framework for the diagnosis and management of patients with acute myelopathy. Additionally, we review the state of current knowledge about the epidemiology, natural history, immunopathogenesis, and treatment strategies for patients with TM. CONCLUSIONS: Our understanding of the classification, diagnosis, pathogenesis, and treatment of TM has recently begun to expand dramatically. With more rigorous criteria applied to distinguish acute myelopathies and with an emerging understanding of immunopathogenic events that underlie TM, it may now be possible to effectively initiate treatments in many of these disorders. Through the investigation of TM, we are also gaining a broader appreciation of the mechanisms that lead to autoimmune neurologic diseases in general.

Unkind cytokines: current evidence for the potential role of cytokines in immune-mediated depression.

A great deal of interest has recently become focused on interactions between the nervous and the immune systems, including the potential for alterations in immune function to contribute to various psychiatric and neurologic disorders. Evidence suggests that cytokines may be involved in the development of depression. Immune-mediated mechanisms in the pathophysiology of some types of depression are reviewed from both clinical and animal studies and the difficulties inherent in studying the interplay of these two complex systems in the development of depression are described.