Combining Neuropsychological Assessment with Neuroimaging to Distinguish Early-Stage Alzheimer's Disease from Frontotemporal Lobar Degeneration in Non-Western Tonal Native Language-Speaking Individuals Living in Taiwan: A Case Series.

Neuropsychological tests (NPTs), which are routinely used in clinical practice for assessment of dementia, are also considered to be essential for differential diagnosis of Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD), especially the behavioral variants of frontotemporal dementia (bvFTD) and primary progressive aphasia (PPA) at their initial clinical presentations. However, the heterogeneous features of these diseases, which have many overlapping signs, make differentiation between AD and FTLD highly challenging. Moreover, NPTs were primarily developed in Western countries and for native speakers of non-tonal languages. Hence, there is an ongoing dispute over the validity and reliability of these tests in culturally different and typologically diverse language populations. The purpose of this case series was to examine which of the NPTs adjusted for Taiwanese society may be used to distinguish these two diseases. Since AD and FTLD have different effects on individuals' brain, we combined NPTs with neuroimaging. We found that participants diagnosed with FTLD had lower scores in NPTs assessing language or social cognition than AD participants. PPA participants also had lower measures in the Free and Cued Selective Reminding Test than those diagnosed with bvFTD, while bvFTD participants showed poorer performances in the behavioral measures than PPA participants. In addition, the initial diagnosis was supported by the standard one-year clinical follow-up.

Biological mechanisms and possible primary prevention of depression.

Individuals with unipolar depressive disorder (UDD) are having an increased risk of death and development of dementia in later life. It is widely expected that in a near future UDD would be the leading cause of death; therefore, a primary inexpensive prevention of UDD will be of a great importance to the society. Several studies provide evidences supporting the positive effect of Mediterranean diet on a reduced risk for development of depression.

Protein adsorption by nanomechanical mass spectrometry: Beyond the real-time molecular weighting.

During past decades, enormous progress in understanding the mechanisms of the intermolecular interactions between the protein and surface at the single-molecule level has been achieved. These advances could only be possible by the ongoing development of highly sophisticated experimental methods such as atomic force microscopy, optical microscopy, surface plasmon resonance, ellipsometry, quartz crystal microbalance, conventional mass spectrometry, and, more recently, the nanomechanical systems. Here, we highlight the main findings of recent studies on the label-free single-molecule (protein) detection by nanomechanical systems including those focusing on the protein adsorption on various substrate surfaces. Since the nanomechanical techniques are capable of detecting and manipulating proteins even at the single-molecule level, therefore, they are expected to open a new way of studying the dynamics of protein functions. It is noteworthy that, in contrast to other experimental methods, where only given protein properties like molecular weight or protein stiffness can be determined, the nanomechanical systems enable a real-time measurement of the multiple protein properties (e.g., mass, stiffness, and/or generated surface stress), making them suitable for the study of protein adsorption mechanisms. Moreover, we also discuss the possible future trends in label-free detection and analysis of dynamics of protein complexes with these nanomechanical systems.

Association of Late Life Depression, (Non-) Modifiable Risk and Protective Factors with Dementia and Alzheimer's Disease: Literature Review on Current Evidences, Preventive Interventions and Possible Future Trends in Prevention and Treatment of Dementia.

The number of people living with dementia and Alzheimer's disease is growing rapidly, making dementia one of the biggest challenges for this century. Many studies have indicated that depression plays an important role in development of dementia, including Alzheimer's disease; depression, especially, during the late life may either increase the risk of dementia or even being its prodromal stage. Despite a notably large number of carried observational studies and/or clinical trials, the association between the late life depression and dementia remains, due to the complexity of their relationship, still unclear. Moreover, during past two decades multiple other (non-)modifiable risk and possibly protective factors such as the hypertension, social engagement, obesity, level of education or physical (in)activity have been identified and their relationship with the risk for development of dementia and Alzheimer's disease has been extensively studied. It has been proposed that to understand mechanisms of dementia and Alzheimer's disease pathogeneses require their multifactorial nature represented by these multiple factors to be considered. In this review, we first summarize the recent literature findings on roles of the late life depression and the other known (non-)modifiable risk and possibly protective factors in development of dementia and Alzheimer's disease. Then, we provide evidences supporting hypotheses that (i) depressive syndromes in late life may indicate the prodromal stage of dementia (Alzheimer's disease) and, (ii) the interplay among the multiple (non-)modifiable risk and protective factors should be considered to gain a better understanding of dementia and Alzheimer's disease pathogeneses. We also discuss the evidences of recently established interventions considered to prevent or delay the prodromes of dementia and provide the prospective future directions in prevention and treatment of dementia and Alzheimer's disease using both the single-domain and multidomain interventions.

Mass Spectrometry of Heavy Analytes and Large Biological Aggregates by Monitoring Changes in the Quality Factor of Nanomechanical Resonators in Air.

Nanomechanical resonators are routinely used for identification of various analytes such as biological and chemical molecules, viruses, or bacteria cells from the frequency response. This identification based on the multimode frequency shift measurement is limited to the analyte of mass that is much lighter than the resonator mass. Hence, the analyte can be modeled as a point particle and, as such, its stiffness and nontrivial binding effects such as surface stress can be neglected. For heavy analytes (>MDa), this identification, however, leads to incorrectly estimated masses. Using a well-known frequency response of the nanomechanical resonator in air, we show that the heavy analyte can be identified without a need for highly challenging analysis of the analyte position, stiffness, and/or binding effects just by monitoring changes in the quality factor (Q-factor) of a single harmonic frequency. A theory with a detailed procedure of mass extraction from the Q-factor is developed. In air, the Q-factor depends on the analyte mass and known air damping, while the impact of the intrinsic dissipation is negligibly small. We find that the highest mass sensitivity (for considered resonator dimensions ∼zg) can be achieved for the rarely measured lateral mode, whereas the commonly detected flexural mode yields the lowest sensitivity. Validity of the proposed procedure is confirmed by extracting the mass of heavy analytes (>GDa) made of protein and Escherichia coli bacteria cells, and the ragweed pollen nanoparticle adsorbed on the surface of the nanomechanical resonator(s) in air, of which the required changes in the Q-factor were previously experimentally measured. Our results open a doorway for rapid detection of viruses and bacteria cells using standard nanomechanical mass sensors.

Association Between Obstructive Sleep Apnea, Its Treatment, and Alzheimer's Disease: Systematic Mini-Review.

Obstructive sleep apnea (OSA) and Alzheimer's disease (AD) are common in the elderly population. Obstructive sleep apnea that may cause significant changes in the cerebrospinal fluid ß-amyloid and T-tau and/or P-tau protein levels is often identified as a risk factor for development of AD. Although the underlying mechanisms of AD are still not fully understood, a hypothesis associating OSA with AD has been already proposed. In this systematic mini-review, we first discuss the recent findings supporting the association of OSA with an increased risk of AD and then provide evidence suggesting the positive effect of OSA treatment on a reduced risk of AD.

Identification of CalDAG-GEFI as an intracellular target for the vicinal dithiol binding agent phenylarsine oxide in human platelets.

CalDAG-GEFI, a guanine nucleotide exchange factor activating Rap1, is known to play a key role in Ca2+-dependent glycoprotein (GP)IIb/IIIa activation and platelet aggregation. Although inhibition of CalDAG-GEFI could be a potential strategy for antiplatelet therapy, no inhibitor of this protein has been identified. In the present study, phenylarsine oxide (PAO), a vicinal dithiol blocker, potently prevented Rap1 activation in thrombin-stimulated human platelets without significantly inhibiting intracellular Ca2+ mobilisation and protein kinase C activation. PAO also prevented the Ca2+ ionophore-induced Rap1 activation and platelet aggregation, which are dependent on CalDAG-GEFI. In the biotin-streptavidin pull-down assay, CalDAG-GEFI was efficiently pull-downed by streptavidin beads from the lysates of biotin-conjugated PAO-treated platelets, suggesting that PAO binds to intracellular CalDAG-GEFI with high affinity. The above effects of PAO were reversed by a vicinal dithiol compound 2,3-dimercaptopropanol. In addition, CalDAG-GEFI formed disulfide-linked oligomers in platelets treated with the thiol-oxidant diamide, indicating that CalDAG-GEFI contains redox-sensitive thiols. In a purified recombinant protein system, PAO directly inhibited CalDAG-GEFI-stimulated GTP binding to Rap1. Using CalDAG-GEFI and Rap1-overexpressed human embryonic kidney 293T cells, we further confirmed that PAO abolished Ca2+-mediated Rap1 activation. Taken together, these results have demonstrated that CalDAG-GEFI is one of the targets of action of PAO, and propose an important role of vicinal cysteines for the functions of CalDAG-GEFI.

Sulforaphane prevents human platelet aggregation through inhibiting the phosphatidylinositol 3-kinase/Akt pathway.

Sulforaphane, a dietary isothiocyanate found in cruciferous vegetables, has been shown to exert beneficial effects in animal models of cardiovascular diseases. However, its effect on platelet aggregation, which is a critical factor in arterial thrombosis, is still unclear. In the present study, we show that sulforaphane inhibited human platelet aggregation caused by different receptor agonists, including collagen, U46619 (a thromboxane A2 mimic), protease-activated receptor 1 agonist peptide (PAR1-AP), and an ADP P2Y12 receptor agonist. Moreover, sulforaphane significantly reduced thrombus formation on a collagen-coated surface under whole blood flow conditions. In exploring the underlying mechanism, we found that sulforaphane specifically prevented phosphatidylinositol 3-kinase (PI3K)/Akt signalling, without markedly affecting other signlaling pathways involved in platelet aggregation, such as protein kinase C activation, calcium mobilisation, and protein tyrosine phosphorylation. Although sulforaphane did not directly inhibit the catalytic activity of PI3K, it caused ubiquitination of the regulatory p85 subunit of PI3K, and prevented PI3K translocation to membranes. In addition, sulforaphane caused ubiquitination and degradation of phosphoinositide-dependent kinase 1 (PDK1), which is required for Akt activation. Therefore, sulforaphane is able to inhibit the PI3K/Akt pathway at two distinct sites. In conclusion, we have demonstrated that sulforaphane prevented platelet aggregation and reduced thrombus formation in flow conditions; our data also support that the inhibition of the PI3K/Akt pathway by sulforaphane contributes it antiplatelet effects.