On the conundrum of cognitive impairment due to depressive disorder in older patients.

OBJECTIVES: Depressive symptoms and cognitive impairment often concur in older persons. Differentiating the cause of cognitive impairment in older persons with Depressive Disorder (DD) from other diseases such as Alzheimer's Disease (AD) is challenging. The goal of this study was to characterize cognitive impairment in older persons with DD. DESIGN: Cross-sectional retrospective observational clinical cohort study using patient records from 2014 to 2018. SETTING: Gerontopsychiatric services of Ulm University at Bezirkskrankenhaus Günzburg serving as primary psychiatric care institution and tertiary referral center for psychiatric care for older persons. PARTCIPANTS: DD was diagnosed according to ICD-10 criteria. When indicated by the medical history or neuropsychological assessment further diagnostic procedures were initiated. Cerebrospinal fluid (CSF) tap was routinely the first additional procedure. If patients did not consent to CSF tap or contraindications were present, 18F-fluordesoxyglucose-PET (FDG-PET) or Amyloid-PET (Am-PET) were performed. MATERIALS AND METHODS: Extensive neuropsychological test battery to assess cognitive profile. RESULTS: 457 subjects were diagnosed with DD (DD-all; age 50-94; 159 males, 298 females). Biomarkers were assessed in 176 persons; in 90 of these subjects AD-biomarkers were negative (DD-BM-; age 54-89; 40 males, 50 females), and in 86 subjects at least one biomarker was compatible with AD (DD-BM+; age 60-90; 31 males, 55 females). Cognitive performance was below healthy controls (HC; n = 56; age 50-80; 30 males, 26 females) for all groups of patients with DD. With case-control matching of HC and DD-BM- we find that executive functions are impaired in about one out of three and delayed recall in about two out of three patients with DD. CONCLUSION: Cognitive impairment is frequent in older persons with DD. Cognitive profile in older patients with DD without and with biomarkers of AD is not distinguishable. Therefore, cognitive impairment due to DD should be diagnosed after exclusion of comorbid AD.

Cognitive profiles in persons with depressive disorder and Alzheimer's disease.

Alzheimer's disease and depressive disorder are frequent in old age. Both may be associated with depressed mood and cognitive impairment. Therefore, finding a strategy to clarify the diagnosis underlying subjective complaints of impaired cognition and depressed mood in older persons is of utmost interest. We conducted a cross-sectional retrospective observational clinical cohort study using patient records from 2014 to 2018. From 3758 patients, we included patients aged 60 years and older with a Mini-Mental-Status Examination score of 24 and above. Final analysis included all patients in whom Alzheimer's disease biomarker analysis was performed (cerebrospinal fluid markers of Alzheimer's disease or positron emission tomography imaging; n = 179) and patients with depressive disorder in whom Alzheimer's disease was ruled out by analysis of biomarkers suggestive of Alzheimer's disease (n = 70). With case-control matching for age, education and gender, performance of patients with Alzheimer's disease was worse in acquisition, consolidation and recall of verbal information and false-positive answers. None of the results, however, sufficed to differentially diagnose individual patients with Alzheimer's disease or depressive disorder. With more severe symptoms of depression, patients with biomarker-verified Alzheimer's disease performed worse in executive testing but were not additionally impaired in verbal episodic memory performance. We conclude that distinguishing between Alzheimer's disease and depressive disorder is unreliable on clinical grounds and behavioural testing alone. Diagnosing the cause of subjective complaints about deteriorating cognitive function or depressed mood requires additional biomarker assessment, whereas cognitive assessment is needed to define appropriate targets of symptomatic treatment in patients with Alzheimer's disease and depressive disorder.

Morphological adaptation of the calamistrum to the cribellate spinning process in Deinopoidae (Uloboridae, Deinopidae).

Spiders are famous for their silk with fascinating mechanical properties. However, some can further produce, process and handle nano fibres, which are used as capture threads. These 'cribellate spiders' bear a specialized setae comb on their metatarsus (calamistrum), which modifies cribellate nano fibres to assemble a puffy structure within the capture thread. Among different species, the calamistrum morphology can differ remarkably. Although a model of thread production has been established for Uloborus plumipes, it is not resolved if/how different shaped calamistra influence the production process. We were able to transfer the model without restrictions to spiders with different shaped calamistra. Fibres are not locked between setae but are passing across a rather smooth surface-like area on the calamistrum. This area can be relocated, explaining the first morphological difference between calamistra, without changing the influence of the calamistrum on fibres. By performing an elongated leg movement, contact between fibres and calamistrum could be adjusted after finishing thread production. This movement has to bring the thread in contact with the second morphological peculiarity: cribellate teeth. We suggest these teeth are used to handle the thread independently of the spinnerets, a feature only necessary for spiders, which do not move during web construction.

Cribellate thread production in spiders: Complex processing of nano-fibres into a functional capture thread.

Spider silk production has been studied intensively in the last years. However, capture threads of cribellate spiders employ an until now often unnoticed alternative of thread production. This thread in general is highly interesting, as it not only involves a controlled arrangement of three types of threads with one being nano-scale fibres (cribellate fibres), but also a special comb-like structure on the metatarsus of the fourth leg (calamistrum) for its production. We found the cribellate fibres organized as a mat, enclosing two parallel larger fibres (axial fibres) and forming the typical puffy structure of cribellate threads. Mat and axial fibres are punctiform connected to each other between two puffs, presumably by the action of the median spinnerets. However, this connection alone does not lead to the typical puffy shape of a cribellate thread. Removing the calamistrum, we found a functional capture thread still being produced, but the puffy shape of the thread was lost. Therefore, the calamistrum is not necessary for the extraction or combination of fibres, but for further processing of the nano-scale cribellate fibres. Using data from Uloborus plumipes we were able to develop a model of the cribellate thread production, probably universally valid for cribellate spiders.

Determination of the Young's modulus of the epicuticle of the smooth adhesive organs of Carausius morosus using tensile testing.

Adhesive organs like arolia of insects allow these animals to climb on different substrates by creating high adhesion forces. According to the Dahlquist criterion, adhesive organs must be very soft, exhibiting an effective Young's modulus of below 100 kPa to adhere well to substrates. Such a low effective Young's modulus allows the adhesive organs to make almost direct contact with the substrate and results in van der Waals forces along with capillary forces. In previous studies, the effective Young's moduli of adhesive organs were determined using indentation tests, revealing their structure to be very soft. However, adhesive organs show a layered structure, thus the measured values comprise the effective Young's moduli of several layers of the adhesive organs. In this study, a new approach is illustrated to measure the Young's modulus of the outermost layer of the arolium, i.e. of the epicuticle, of the stick insect Carausius morosus. As a result of the epicuticle being supported by upright fibres, tensile tests allow the determination of the Young's modulus of the epicuticle with hardly influence from subjacent layers. In our tensile tests, arolia of stick insects adhering on a latex membrane were stretched by stretching the membrane while the elongation of the contact area between an arolium and the membrane was recorded. For analysis, mathematical models of the mechanical system were developed. When fed with the observed elongations, these models yield estimates for the Young's modulus of the epicuticle of approximately 100 MPa. Thus, in arolia, a very thin layer (~225 nm) of a rather stiff material, which is less susceptible to abrasion, makes contact with the substrates, whereas the inner fibrous structure of arolia is responsible for their softness.

Improved decoupling during symmetry-based C9-TOBSY sequences.

We show that heteronuclear decoupling during symmetry-based C9 TOBSY sequences can be improved by using phase-alternating pulse sequences (XiX) instead of cw irradiation. The use of XiX sequences makes the optimization of the decoupling rf-field amplitude simpler and lowers the decoupling rf-field requirements to attain a comparable performance. A Floquet analysis of the first-order resonance conditions was used to determine the correct timing of the XiX sequence to avoid interference between the C sequence and the decoupling. The decoupling performance is analyzed analytically using Floquet theory and verified using numerical simulations as well as experimental results.

PAIN with and without PAR: variants for third-spin assisted heteronuclear polarization transfer.

In this article, we describe third-spin assisted heteronuclear recoupling experiments, which play an increasingly important role in measuring long-range heteronuclear couplings, in particular (15)N-(13)C, in proteins. In the proton-assisted insensitive nuclei cross polarization (PAIN-CP) experiment (de Paëpe et al. in J Chem Phys 134:095101, 2011), heteronuclear polarization transfer is always accompanied by homonuclear transfer of the proton-assisted recoupling (PAR) type. We present a phase-alternating experiment that promotes heteronuclear (e.g. (15)N → (13)C) polarization transfer while simultaneously minimizing homonuclear (e.g.(13)C → (13)C) transfer (PAIN without PAR). This minimization of homonuclear polarization transfer is based on the principle of the resonant second-order transfer (RESORT) recoupling scheme where the passive proton spins are irradiated by a phase-alternating sequence and the modulation frequency is matched to an integer multiple of the spinning frequency. The similarities and differences between the PAIN-CP and this het-RESORT experiment are discussed here.

Operator-based Floquet theory in solid-state NMR.

This article reviews the application of operator-based Floquet theory in solid-state NMR. Basic expressions for calculating effective Hamiltonians based on van Vleck perturbation theory are reviewed for problems with a single frequency or multiple incommensurate frequencies. Such a treatment allows calculation of effective Hamiltonians for resonant and non-resonant problems. Examples from literature are given for single-mode to triple-mode Floquet problems, covering a wide range of applications in solid-state NMR under magic-angle spinning and radio-frequency irradiation of a single nucleus or multiple nuclei.

Understanding two-pulse phase-modulated decoupling in solid-state NMR.

A theoretical description of the two-pulse phase-modulated (TPPM) decoupling sequence in magic-angle spinning NMR is presented using a triple-mode Floquet approach. The description is formulated in the radio-frequency interaction-frame representation and is valid over the entire range of possible parameters leading to the well-known results of continuous-wave (cw) decoupling and XiX decoupling in the limit of a phase change of 0 degrees and 180 degrees , respectively. The treatment results in analytical expressions for the heteronuclear residual coupling terms and the homonuclear spin-diffusion terms. It also allows the characterization of all resonance conditions that can contribute in a constructive or a destructive way to the residual linewidth. Some of the important resonance conditions are described for the first time since they are not accessible in previous treatments. The combination of the contributions from the residual couplings and the resonance conditions to the effective Hamiltonian, as obtained in a Floquet description, is shown to be required to describe the decoupling behavior over the full range of parameters. It is shown that for typical spin system and experimental parameters a (13)C linewidth of approximately 12 Hz can be obtained for TPPM decoupling in an organic solid or a protein. This is a major contribution to the experimentally observed linewidths of around 20 Hz and indicates that decoupling techniques are still one of the limiting factors in the achievable linewidths.

Ultrastructure and physical properties of an adhesive surface, the toe pad epithelium of the tree frog, Litoria caerulea White.

Knowledge of both surface structure and physical properties such as stiffness and elasticity are essential to understanding any adhesive system. In this study of an adhesion surface in the tree frog, Litoria caerulea White, a variety of techniques including atomic force microscopy were used to investigate the microstructure and properties of an epithelium that adheres through wet adhesion. Litoria toe pads consist of a hexagonal array of flat-topped epithelial cells, separated by mucus-filled channels. Under an atomic force microscope, this ;flat' surface is highly structured at the nanoscale, consisting of a tightly packed array of columnar nanopillars (described as hemidesmosomes by previous authors), 326+/-84 nm in diameter, each of which possesses a central dimple 8+/-4 nm in depth. In fixed tissue (transmission electron microscopy), the nanopillars are approximately as tall as they are broad. At the gross anatomical level, larger toe pads may be subdivided into medial and lateral parts by two large grooves. Although the whole toe pad is soft and easily deformable, the epithelium itself has an effective elastic modulus equivalent to silicon rubber (mean E(eff)=14.4+/-20.9 MPa; median E(eff)=5.7 MPa), as measured by the atomic force microscope in nanoindentation mode. The functions of these structures are discussed in terms of maximising adhesive and frictional forces by conforming closely to surface irregularities at different length scales and maintaining an extremely thin fluid layer between pad and substrate. The biomimetic implications of these findings are reviewed.

Micromechanics of smooth adhesive organs in stick insects: pads are mechanically anisotropic and softer towards the adhesive surface.

Animals have evolved adhesive structures on their legs to cling to the substrate during locomotion. Here we characterise the ultrastructure and mechanical properties of adhesive pads in Carausius morosus (Phasmatodea) using atomic force microscopy (AFM) as well as transmission and scanning electron microscopy (TEM, SEM). The smooth adhesive arolium has a soft cuticle consisting of principal rods, which branch into finer fibres near the surface. Indentation experiments showed that the pad material consists of distinct layers with different mechanical properties. The 100-300 nm thick outermost layer consisting of the cuticulin envelope and the epicuticle is extremely soft and resilient (mean effective Young's modulus 12 kPa), while the subjacent procuticle is a much stiffer material (mean effective Young's modulus 625 kPa). AFM contact mode imaging revealed that the cuticle is mechanically anisotropic, which can be explained by its fibrillar inner structure. We propose that the described layered structure of smooth adhesive pads, consisting of materials decreasing in stiffness towards the outer surface, represents a superior design to conform and adhere to substrates with roughnesses at different length scales. This design principle could be easily implemented in technical adhesives, and thus has a potential to inspire biomimetic applications.

Operator-based triple-mode Floquet theory in solid-state NMR.

Many solid-state NMR experiments exploit interference effects between time dependencies in the system Hamiltonian to design an effective time-independent Hamiltonian with the desired properties. Effective Hamiltonians can be designed such that they contain only selected parts of the full system Hamiltonian while all other parts are averaged to zero. A general theoretical description of such experiments has to accommodate several time-dependent perturbations with incommensurate frequencies. We describe an extension of the analytical operator-based Floquet description of NMR experiments to situations with three incommensurate frequencies. Experiments with three time dependencies are quite common in solid-state NMR. Examples include experiments which combine magic-angle spinning and radio-frequency irradiation on two nuclei or asynchronous multiple-pulse sequences on a single spin species. The Floquet description is general in the sense that the resulting effective Hamiltonians can be calculated without a detailed knowledge of the spin-system Hamiltonian and can be expressed fully as a function of the Fourier components of the time-dependent Hamiltonian. As a prototype experiment we treat the application of two continuous-wave (cw) radio-frequency fields under magic-angle spinning. Experiments that are included in such a description are Hartmann-Hahn cross polarization or rotary-resonance recoupling experiments with simultaneous cw decoupling.

J-deconvolution using maximum entropy reconstruction applied to 13C-13C solid-state cross-polarization magic-angle-spinning NMR of proteins.

Scalar couplings between 13C spins can impair both resolution and sensitivity in 13C-labeled preparations. It is demonstrated that deconvolution of magic-angle-spinning NMR data with maximum entropy (MaxEnt) reconstruction allows the removal of splittings due to J-couplings without expenses in sensitivity. A combination of MaxEnt reconstruction in t2 with selective pulses in t1 produces fully J-resolved data in both dimensions. The possibility to obtain J-resolved 13C-13C data without compromising the sensitivity is particularly important for solid-state NMR of "difficult" biological samples, like membrane proteins, where sacrifices in signal-to-noise are fatal. The method is demonstrated using preparations of alpha-spectrin SH3 domain (62 residues) as small test system and of outermembrane protein G as example of a membrane protein with higher molecular weight (281 residues). Both preparations were obtained using [2-13C]-glycerol as the carbon source during the bacterial growth.

Electrophoresis in gel channels.

We describe a novel approach to generate dynamic pH gradients suited to fractionate or purify samples of biomolecules or particles such as proteins and viruses in tiny volumes. The method combines diffusion and electromigration between micro-scaled channels embedded in hydrogel. For the used geometry and in accordance with numerical calculations the gel-channel system reaches a tuneable, steady-state pH gradient after a few minutes. For quantification of experimentally generated pH-profiles, the concentration independent extinction ratio of phenol red at two wavelengths is used. The proposed electrophoretic flow-cell is simple and flexible since no Immobilines are required to establish the pH gradient.