Optimizing the post-graduate institutional program evaluation process

Abstract Background Reviewing program educational efforts is an important component of postgraduate medical education program accreditation. The post-graduate review process has evolved over time to include centralized oversight based on accreditation standards. The institutional review process and the impact on participating faculty are topics not well described in the literature. Methods We conducted multiple Plan-Do-Study-Act (PDSA) cycles to identify and implement areas for change to improve productivity in our institutional program review committee. We also conducted one focus group and six in-person interviews with 18 committee members to explore their perspectives on the committee’s evolution. One author (MLL) reviewed the transcripts and performed the initial thematic coding with a PhD level research associate and identified and categorized themes. These themes were confirmed by all participating committee members upon review of a detailed summary. Emergent themes were triangulated with the University of Michigan Medical School’s Admissions Executive Committee (AEC). Results We present an overview of adopted new practices to the educational program evaluation process at the University of Michigan Health System that includes standardization of meetings, inclusion of resident members, development of area content experts, solicitation of committed committee members, transition from paper to electronic committee materials, and focus on continuous improvement. Faculty and resident committee members identified multiple improvement areas including the ability to provide high quality reviews of training programs, personal and professional development, and improved feedback from program trainees. Conclusions A standing committee that utilizes the expertise of a group of committed faculty members and which includes formal resident membership has significant advantages over ad hoc or other organizational structures for program evaluation committees.http://deepblue.lib.umich.edu/bitstream/2027.42/117363/1/12909_2016_Article_586.pd

Preclinical and clinical biomarker studies of CT1812: A novel approach to Alzheimer's disease modification

INTRODUCTION: Amyloid beta (Aβ) oligomers are one of the most toxic structural forms of the Aβ protein and are hypothesized to cause synaptotoxicity and memory failure as they build up in Alzheimer's disease (AD) patients' brain tissue. We previously demonstrated that antagonists of the sigma-2 receptor complex effectively block Aβ oligomer toxicity. CT1812 is an orally bioavailable, brain penetrant small molecule antagonist of the sigma-2 receptor complex that appears safe and well tolerated in healthy elderly volunteers. We tested CT1812's effect on Aβ oligomer pathobiology in preclinical AD models and evaluated CT1812's impact on cerebrospinal fluid (CSF) protein biomarkers in mild to moderate AD patients in a clinical trial (ClinicalTrials.gov NCT02907567). METHODS: Experiments were performed to measure the impact of CT1812 versus vehicle on Aβ oligomer binding to synapses in vitro, to human AD patient post mortem brain tissue ex vivo, and in living APPSwe /PS1dE9 transgenic mice in vivo. Additional experiments were performed to measure the impact of CT1812 versus vehicle on Aβ oligomer-induced deficits in membrane trafficking rate, synapse number, and protein expression in mature hippocampal/cortical neurons in vitro. The impact of CT1812 on cognitive function was measured in transgenic Thy1 huAPPSwe/Lnd+ and wild-type littermates. A multicenter, double-blind, placebo-controlled parallel group trial was performed to evaluate the safety, tolerability, and impact on protein biomarker expression of CT1812 or placebo given once daily for 28 days to AD patients (Mini-Mental State Examination 18-26). CSF protein expression was measured by liquid chromatography with tandem mass spectrometry or enzyme-linked immunosorbent assay in samples drawn prior to dosing (Day 0) and at end of dosing (Day 28) and compared within each patient and between pooled treated versus placebo-treated dosing groups. RESULTS: CT1812 significantly and dose-dependently displaced Aβ oligomers bound to synaptic receptors in three independent preclinical models of AD, facilitated oligomer clearance into the CSF, increased synaptic number and protein expression in neurons, and improved cognitive performance in transgenic mice. CT1812 significantly increased CSF concentrations of Aβ oligomers in AD patient CSF, reduced concentrations of synaptic proteins and phosphorylated tau fragments, and reversed expression of many AD-related proteins dysregulated in CSF. DISCUSSION: These preclinical studies demonstrate the novel disease-modifying mechanism of action of CT1812 against AD and Aβ oligomers. The clinical results are consistent with preclinical data and provide evidence of target engagement and impact on fundamental disease-related signaling pathways in AD patients, supporting further development of CT1812

Tau Causes Synapse Loss without Disrupting Calcium Homeostasis in the rTg4510 Model of Tauopathy

Neurofibrillary tangles (NFTs) of tau are one of the defining hallmarks of Alzheimer’s disease (AD), and are closely associated with neuronal degeneration. Although it has been suggested that calcium dysregulation is important to AD pathogenesis, few studies have probed the link between calcium homeostasis, synapse loss and pathological changes in tau. Here we test the hypothesis that pathological changes in tau are associated with changes in calcium by utilizing in vivo calcium imaging in adult rTg4510 mice that exhibit severe tau pathology due to over-expression of human mutant P301L tau. We observe prominent dendritic spine loss without disruptions in calcium homeostasis, indicating that tangles do not disrupt this fundamental feature of neuronal health, and that tau likely induces spine loss in a calcium-independent manner

Tau pathology does not affect experience-driven single-neuron and network-wide Arc/Arg3.1 responses

Intraneuronal neurofibrillary tangles (NFTs) – a characteristic pathological feature of Alzheimer’s and several other neurodegenerative diseases – are considered a major target for drug development. Tangle load correlates well with the severity of cognitive symptoms and mouse models of tauopathy are behaviorally impaired. However, there is little evidence that NFTs directly impact physiological properties of host neurons. Here we used a transgenic mouse model of tauopathy to study how advanced tau pathology in different brain regions affects activity-driven expression of immediate-early gene Arc required for experience-dependent consolidation of long-term memories. We demonstrate in vivo that visual cortex neurons with tangles are as likely to express comparable amounts of Arc in response to structured visual stimulation as their neighbors without tangles. Probability of experience-dependent Arc response was not affected by tau tangles in both visual cortex and hippocampal pyramidal neurons as determined postmortem. Moreover, whole brain analysis showed that network-wide activity-driven Arc expression was not affected by tau pathology in any of the brain regions, including brain areas with the highest tangle load. Our findings suggest that intraneuronal NFTs do not affect signaling cascades leading to experience-dependent gene expression required for long-term synaptic plasticity

Are tangles as toxic as they look?

Neurofibrillary tangles are intracellular accumulations of hyperphosphorylated and misfolded tau protein characteristic of Alzheimer's disease and other tauopathies. Classic cross-sectional studies of Alzheimer patient brains showed associations of tangle accumulation with neuronal loss, synapse loss, and dementia, which led to the supposition that tangles are toxic to neurons. More recent advances in imaging techniques and mouse models have allowed the direct exploration of the question of toxicity of aggregated versus soluble tau and have surprisingly challenged the view of tangles as toxic species in the brain. Here, we review these recent experiments on the nature of the toxicity of tau with particular emphasis on our experiments imaging tangles in the intact brain through a cranial window, which allows observation of tangle formation and longitudinal imaging of the fate of tangle-bearing neurons. Neurofibrillary tangles (NFT) were first described in 1906 by Alois Alzheimer based on Bielschowsky silver staining of the brain of his demented patient Auguste D (Alzheimer 1907; Goedert and Spillantini 2006). These intraneuronal aggregates have subsequently been found to be composed primarily of hyperphosphorylated tau protein and are definitive pathological lesions not only in Alzheimer's disease but also in a class of neurodegenerative tauopathies (Goedert et al. 1988; Spires-Jones et al. 2009). NFT pathology in Alzheimer's disease (AD) correlates closely with cognitive decline and synapse and neuronal loss (Braak and Braak 1997; Bretteville and Planel 2008; Congdon and Duff 2008; Mocanu et al. 2008b; Spires-Jones et al. 2009). As a result, NFT have long been considered indicative of impending neuronal cell death. More recent evidence, however, opposes this classical view. Here we review evidence addressing the question of whether NFT cause structural or functional neuronal damage

Studying synapses in human brain with array tomography and electron microscopy

Postmortem studies of synapses in human brain are problematic due to the axial resolution limit of light microscopy and the difficulty preserving and analyzing ultrastructure with electron microscopy. Array tomography overcomes these problems by embedding autopsy tissue in resin and cutting ribbons of ultrathin serial sections. Ribbons are imaged with immunofluorescence, allowing high-throughput imaging of tens of thousands of synapses to assess synapse density and protein composition. The protocol takes approximately 3 days per case, excluding image analysis, which is done at the end of the study. Parallel processing for transmission electron microscopy (TEM) using a protocol modified to preserve structure in human samples allows complimentary ultrastructural studies. Incorporation of array tomography and TEM into brain banking is a potent way of phenotyping synapses in well-characterized clinical cohorts to develop clinico-pathological correlations at the synapse level. This will be important for research in neurodegenerative disease, developmental diseases, and psychiatric illness

Orally Administrated Cinnamon Extract Reduces β-Amyloid Oligomerization and Corrects Cognitive Impairment in Alzheimer's Disease Animal Models

An increasing body of evidence indicates that accumulation of soluble oligomeric assemblies of β-amyloid polypeptide (Aβ) play a key role in Alzheimer's disease (AD) pathology. Specifically, 56 kDa oligomeric species were shown to be correlated with impaired cognitive function in AD model mice. Several reports have documented the inhibition of Aβ plaque formation by compounds from natural sources. Yet, evidence for the ability of common edible elements to modulate Aβ oligomerization remains an unmet challenge. Here we identify a natural substance, based on cinnamon extract (CEppt), which markedly inhibits the formation of toxic Aβ oligomers and prevents the toxicity of Aβ on neuronal PC12 cells. When administered to an AD fly model, CEppt rectified their reduced longevity, fully recovered their locomotion defects and totally abolished tetrameric species of Aβ in their brain. Furthermore, oral administration of CEppt to an aggressive AD transgenic mice model led to marked decrease in 56 kDa Aβ oligomers, reduction of plaques and improvement in cognitive behavior. Our results present a novel prophylactic approach for inhibition of toxic oligomeric Aβ species formation in AD through the utilization of a compound that is currently in use in human diet

Metal Ionophore Treatment Restores Dendritic Spine Density and Synaptic Protein Levels in a Mouse Model of Alzheimer's Disease

We have previously demonstrated that brief treatment of APP transgenic mice with metal ionophores (PBT2, Prana Biotechnology) rapidly and markedly improves learning and memory. To understand the potential mechanisms of action underlying this phenomenon we examined hippocampal dendritic spine density, and the levels of key proteins involved in learning and memory, in young (4 months) and old (14 months) female Tg2576 mice following brief (11 days) oral treatment with PBT2 (30 mg/kg/d). Transgenic mice exhibited deficits in spine density compared to littermate controls that were significantly rescued by PBT2 treatment in both the young (+17%, p<0.001) and old (+32%, p<0.001) animals. There was no effect of PBT2 on spine density in the control animals. In the transgenic animals, PBT2 treatment also resulted in significant increases in brain levels of CamKII (+57%, p = 0.005), spinophilin (+37%, p = 0.04), NMDAR1A (+126%, p = 0.02), NMDAR2A (+70%, p = 0.05), pro-BDNF (+19%, p = 0.02) and BDNF (+19%, p = 0.04). While PBT2-treatment did not significantly alter neurite-length in vivo, it did increase neurite outgrowth (+200%, p = 0.006) in cultured cells, and this was abolished by co-incubation with the transition metal chelator, diamsar. These data suggest that PBT2 may affect multiple aspects of snaptic health/efficacy. In Alzheimer's disease therefore, PBT2 may restore the uptake of physiological metal ions trapped within extracellular β-amyloid aggregates that then induce biochemical and anatomical changes to improve cognitive function

Efficient RT-QuIC seeding activity for \u3b1-synuclein in olfactory mucosa samples of patients with Parkinson's disease and multiple system atrophy

Background: Parkinson's disease (PD) is a neurodegenerative disorder whose diagnosis is often challenging because symptoms may overlap with neurodegenerative parkinsonisms. PD is characterized by intraneuronal accumulation of abnormal \u3b1-synuclein in brainstem while neurodegenerative parkinsonisms might be associated with accumulation of either \u3b1-synuclein, as in the case of Multiple System Atrophy (MSA) or tau, as in the case of Corticobasal Degeneration (CBD) and Progressive Supranuclear Palsy (PSP), in other disease-specific brain regions. Definite diagnosis of all these diseases can be formulated only neuropathologically by detection and localization of \u3b1-synuclein or tau aggregates in the brain. Compelling evidence suggests that trace-amount of these proteins can appear in peripheral tissues, including receptor neurons of the olfactory mucosa (OM). Methods: We have set and standardized the experimental conditions to extend the ultrasensitive Real Time Quaking Induced Conversion (RT-QuIC) assay for OM analysis. In particular, by using human recombinant \u3b1-synuclein as substrate of reaction, we have assessed the ability of OM collected from patients with clinical diagnoses of PD and MSA to induce \u3b1-synuclein aggregation, and compared their seeding ability to that of OM samples collected from patients with clinical diagnoses of CBD and PSP. Results: Our results showed that a significant percentage of MSA and PD samples induced \u3b1-synuclein aggregation with high efficiency, but also few samples of patients with the clinical diagnosis of CBD and PSP caused the same effect. Notably, the final RT-QuIC aggregates obtained from MSA and PD samples owned peculiar biochemical and morphological features potentially enabling their discrimination. Conclusions: Our study provide the proof-of-concept that olfactory mucosa samples collected from patients with PD and MSA possess important seeding activities for \u3b1-synuclein. Additional studies are required for (i) estimating sensitivity and specificity of the technique and for (ii) evaluating its application for the diagnosis of PD and neurodegenerative parkinsonisms. RT-QuIC analyses of OM and cerebrospinal fluid (CSF) can be combined with the aim of increasing the overall diagnostic accuracy of these diseases, especially in the early stages