Although the hippocampus is one of the most studied structures in the human brain, limited quantitative data exist on its 3D organization, anatomical variability, and effects of disease on its ...subregions. Histological studies provide restricted reference information due to their 2D nature. In this paper, high-resolution (∼200 × 200 × 200 μm³) ex vivo MRI scans of 31 human hippocampal specimens are combined using a groupwise diffeomorphic registration approach into a 3D probabilistic atlas that captures average anatomy and anatomic variability of hippocampal subfields. Serial histological imaging in 9 of the 31 specimens was used to label hippocampal subfields in the atlas based on cytoarchitecture. Specimens were obtained from autopsies in patients with a clinical diagnosis of Alzheimer’s disease (AD; 9 subjects, 13 hemispheres), of other dementia (nine subjects, nine hemispheres), and in subjects without dementia (seven subjects, nine hemispheres), and morphometric analysis was performed in atlas space to measure effects of age and AD on hippocampal subfields. Disproportional involvement of the cornu ammonis (CA) 1 subfield and stratum radiatum lacunosum moleculare was found in AD, with lesser involvement of the dentate gyrus and CA2/3 subfields. An association with age was found for the dentate gyrus and, to a lesser extent, for CA1. Three-dimensional patterns of variability and disease and aging effects discovered via the ex vivo hippocampus atlas provide information highly relevant to the active field of in vivo hippocampal subfield imaging.
Medial temporal lobe (MTL) substructures are the earliest regions affected by neurofibrillary tangle pathology—and thus are promising biomarkers for Alzheimer's disease (AD). However, automatic ...segmentation of the MTL using only T1‐weighted (T1w) magnetic resonance imaging (MRI) is challenging due to the large anatomical variability of the MTL cortex and the confound of the dura mater, which is commonly segmented as gray matter by state‐of‐the‐art algorithms because they have similar intensity in T1w MRI. To address these challenges, we developed a novel atlas set, consisting of 15 cognitively normal older adults and 14 patients with mild cognitive impairment with a label explicitly assigned to the dura, that can be used by the multiatlas automated pipeline (Automatic Segmentation of Hippocampal Subfields ASHS‐T1) for the segmentation of MTL subregions, including anterior/posterior hippocampus, entorhinal cortex (ERC), Brodmann areas (BA) 35 and 36, and parahippocampal cortex on T1w MRI. Cross‐validation experiments indicated good segmentation accuracy of ASHS‐T1 and that the dura can be reliably separated from the cortex (6.5% mislabeled as gray matter). Conversely, FreeSurfer segmented majority of the dura mater (62.4%) as gray matter and the degree of dura mislabeling decreased with increasing disease severity. To evaluate its clinical utility, we applied the pipeline to T1w images of 663 ADNI subjects and significant volume/thickness loss is observed in BA35, ERC, and posterior hippocampus in early prodromal AD and all subregions at later stages. As such, the publicly available new atlas and ASHS‐T1 could have important utility in the early diagnosis and monitoring of AD and enhancing brain‐behavior studies of these regions.
...the locations of the boundaries between subfields in this segmentation protocol are in mismatch with the anatomical atlases in a large part of the long axis. Several segmentation methods exist ...also for T2 images, manual (La Joie et al., 2010; Wisse et al., 2012) as well as automated (Yushkevich et al., 2009). Because of the complex anatomy of the hippocampal head and tail, these methods either limit the segmentation of subfields to the hippocampal body (Mueller et al., 2007; Yushkevich et al., 2009) or developed a separate segmentation scheme for the head and/or tail (La Joie et al., 2010; Wisse et al., 2012; Winterburn et al., 2013). To the best of our knowledge, the protocol was not validated against a manual segmentation on these lower resolutions 1.5–3 T MR images (see also Lim et al., 2012; Pluta et al., 2012). ...it should be noted that the intra-rater reliability of the manual segmentation used for the FreeSurfer package was based on repeated segmentation of two coronal slices rather than on segmentation of the complete long axis of the hippocampus (Van Leemput et al., 2009). ...though FreeSurfer provides a useful, broad set of automated brain MRI analysis tools, we have concerns about the current package for automated hippocampal subfield segmentation.
In the Multi beam source (MBS) of our Multi Beam Scanning Electron Microscope (MBSEM), an aperture lens array (ALA) splits the emission cone of the Schottky field emitter into multiple beamlets. When ...the apertures in the ALA are close to each other, the ALA can introduce aberrations to these beamlets through the electrostatic interaction of neighbouring apertures with each aperture's lens field. When the apertures are arranged in a square grid pattern, the aberration causes fourfold astigmatism. The effect on the beam spot is analyzed through a combination of 3D simulations and experimental validation. To counterbalance the fourfold astigmatism, a correction scheme is proposed in which a slightly non-round profile is applied to the aperture lenses.
Crucial to the success of clinical trials targeting early Alzheimer's disease (AD) is recruiting participants who are more likely to progress over the course of the trials. We hypothesize that a ...combination of plasma and structural MRI biomarkers, which are less costly and non-invasive, is predictive of longitudinal progression measured by atrophy and cognitive decline in early AD, providing a practical alternative to PET or cerebrospinal fluid biomarkers.
Longitudinal T1-weighted MRI, cognitive (memory-related test scores and clinical dementia rating scale), and plasma measurements of 245 cognitively normal (CN) and 361 mild cognitive impairment (MCI) patients from ADNI were included. Subjects were further divided into β-amyloid positive/negative (Aβ+/Aβ-) subgroups. Baseline plasma (p-tau
and neurofilament light chain) and MRI-based structural medial temporal lobe subregional measurements and their association with longitudinal measures of atrophy and cognitive decline were tested using stepwise linear mixed effect modeling in CN and MCI, as well as separately in the Aβ+/Aβ- subgroups. Receiver operating characteristic (ROC) analyses were performed to investigate the discriminative power of each model in separating fast and slow progressors (first and last terciles) of each longitudinal measurement.
A total of 245 CN (35.0% Aβ+) and 361 MCI (53.2% Aβ+) participants were included. In the CN and MCI groups, both baseline plasma and structural MRI biomarkers were included in most models. These relationships were maintained when limited to the Aβ+ and Aβ- subgroups, including Aβ- CN (normal aging). ROC analyses demonstrated reliable discriminative power in identifying fast from slow progressors in MCI area under the curve (AUC): 0.78-0.93 and more modestly in CN (0.65-0.73).
The present data support the notion that plasma and MRI biomarkers, which are relatively easy to obtain, provide a prediction for the rate of future cognitive and neurodegenerative progression that may be particularly useful in clinical trial stratification and prognosis. Additionally, the effect in Aβ- CN indicates the potential use of these biomarkers in predicting a normal age-related decline.
We investigated the association between the administration of phosphodiesterase 3 inhibitors (PDE3i) and lactate kinetics, resolution of organ failure, ICU and hospital length of stay (LOS) and ...hospital mortality in a retrospective cohort of patients with septic shock and persistently elevated lactate concentrations.
Patients with septic shock and two arterial lactate concentrations ≥4 mmol/L with at least 4 h between measurements were eligible. Clinical data of the first four days of admission were collected in an online database. For each patient, the area between the actual lactate concentrations and 2.2 mmol/L (AUClact2.2), was calculated for three days.
Data on 229 patients from 10 hospitals were collected, of whom 123 received PDE3i (54%). First, a linear multivariate model was developed to predict AUClact2.2 (R2 = 0.57). Adding PDE3i as a cofactor did not affect R2. Second, 60 patients receiving PDE3i at any time between days 0 and 2 were compared to 60 propensity matched no-PDE3i patients. Third, 30 patients who received PDE3i from ICU admission to day 3 were compared to 30 propensity-matched no-PDE3i patients. These analyses showed no differences in AUClact2.2, SOFA scores, ICU or hospital LOS or hospital mortality between treatment groups.
No association was found between the administration of PDE3i and lactate kinetics, resolution of organ failure, ICU or hospital LOS or hospital mortality.
•Septic shock patients with persistently elevated lactate levels have an impaired prognosis.•PDE3-inhibitors with ‘ino-dilatatory’ properties,(e.g. milrinone, enoximone, may improve hemodynamics and lactate clearance.•In this study, we found no association between the use of PDE3-inhibitors and an improvement of lactate kinetics.•PDE3-inhibitors did not influence organ failure resolution or survival in septic patients with persistent elevated lactate.
Abstract Background In stroke and multiple sclerosis patients, gait is frequently hampered by a reduced ability to push-off with the ankle caused by weakness of the plantar-flexor muscles. To enhance ...ankle push-off and to decrease the high energy cost of walking, spring-like carbon-composite Ankle Foot Orthoses are frequently prescribed. However, it is unknown what Ankle Foot Orthoses stiffness should be used to obtain the most efficient gait. The aim of this simulation study was to gain insights into the effect of variation in Ankle Foot Orthosis stiffness on the amount of energy stored in the Ankle Foot Orthosis and the energy cost of walking. Methods We developed a two-dimensional forward-dynamic walking model with a passive spring at the ankle representing the Ankle Foot Orthosis and two constant torques at the hip for propulsion. We varied Ankle Foot Orthosis stiffness while keeping speed and step length constant. Findings We found an optimal stiffness, at which the energy delivered at the hip joint was minimal. Energy cost decreased with increasing energy storage in the ankle foot orthosis, but the most efficient gait did not occur with maximal energy storage. With maximum storage, push-off occurred too late to reduce the impact of the contralateral leg with the floor. Maximum return prior to foot strike was also suboptimal, as push-off occurred too early and its effects were subsequently counteracted by gravity. The optimal Ankle Foot Orthosis stiffness resulted in significant push-off timed just prior to foot strike and led to greater ankle plantar-flexion velocity just before contralateral foot strike. Interpretation Our results suggest that patient energy cost might be reduced by the proper choice of Ankle Foot Orthosis stiffness.
Little is known about the heterogeneous etiology of suspected non-Alzheimer's pathophysiology (SNAP), a group of subjects with neurodegeneration in the absence of β-amyloid. Using antemortem MRI and ...pathological data, we investigated the etiology of SNAP and the association of neurodegenerative pathologies with structural medial temporal lobe (MTL) measures in β-amyloid-negative subjects.
Subjects with antemortem MRI and autopsy data were selected from ADNI (n=63) and the University of Pennsylvania (n=156). Pathological diagnoses and semi-quantitative scores of MTL tau, neuritic plaques, α-synuclein, and TDP-43 pathology and MTL structural MRI measures from antemortem T1-weighted MRI scans were obtained. β-amyloid status (A+/A-) was determined by CERAD score and neurodegeneration status (N+/N-) by hippocampal volume.
SNAP reflects a heterogeneous group of pathological diagnoses. In ADNI, SNAP (A-N+) had significantly more neuropathological diagnoses than A+N+. In the A- group, tau pathology was associated with hippocampal, entorhinal cortex, and Brodmann area 35 volume/thickness and TDP-43 pathology with hippocampal volume.
SNAP had a heterogeneous profile with more mixed pathologies than A+N+. Moreover, a role for TDP-43 and tau pathology in driving MTL neurodegeneration in the absence of β-amyloid was supported.
While research on abusive supervision is thriving, we still know very little about the sustained nature of the phenomenon. The scant papers focusing on the prolonged character of the detrimental ...relational dynamic have taken a within-dyad perspective, largely ignoring within-person, group, or other external influences. Addressing these gaps in the literature, we introduce the barriers model of abusive supervision. This model posits a hierarchically organized set of obstacles that make it difficult for followers to escape the abusive supervisor, explaining why abuse can continue over long periods of time. Specifically, we present an onion-type model, in which the follower has a central position and each subsequent layer represents a more external cluster of barriers to leaving the abusive supervisor. Ranging from external to internal, these layers are: barriers in the larger societal context (Layer 1; e.g., ambiguous laws), barriers in the organizational context (Layer 2; e.g., unclear policies), barriers due to the abusive supervisor (Layer 3; e.g., isolating followers), and barriers within the abused follower (Layer 4; e.g., implicit leadership theories). We hope that our model inspires future research on the sustained nature of abusive supervision and provides practitioners with the necessary background information to help abused followers escape their supervisors.
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