Methods to Quantify Nanomaterial Association with, and Distribution across, the Blood-Brain Barrier in Vivo

The role and functional anatomy of the blood-brain barrier (BBB) is summarized to enable the investigator to appropriately address evaluation of nanomaterial interaction with, and distribution across, it into brain tissue (parenchyma). Transport mechanisms across the BBB are presented, in relation to nanomaterial physicochemical properties. Measures and test substances to assess BBB integrity/disruption/permeation are introduced, along with how they are used to interpret the results obtained with the presented methods. Experimental pitfalls and misinterpretation of results of studies of brain nanomaterial uptake are briefly summarized, that can be avoided with the methods presented in this chapter. Two methods are presented. The in situ brain perfusion technique is used to determine rate and extent of nanomaterial distribution into the brain. The capillary depletion method separates brain parenchymal tissue from the endothelial cells that contribute to the BBB. It is used to verify nanomaterial brain tissue entry. These methods are best used together, the latter refining the results obtained with the former. Details of the materials and equipment needed to conduct these methods, and description of the procedures and data interpretation, are provided

Noncovalent Interactions of Hydrated DNA and RNA Mapped by 2D-IR Spectroscopy

Biomolecules couple to their aqueous environment through a variety of noncovalent interactions. Local structures at the surface of DNA and RNA are frequently determined by hydrogen bonds with water molecules, complemented by non-specific electrostatic and many-body interactions. Structural fluctuations of the water shell result in fluctuating Coulomb forces on polar and/or ionic groups of the biomolecular structure and in a breaking and reformation of hydrogen bonds. Two-dimensional infrared (2D-IR) spectroscopy of vibrational modes of DNA and RNA gives insight into local hydration geometries, elementary molecular dynamics, and the mechanisms behind them. In this chapter, recent results from 2D-IR spectroscopy of native and artificial DNA and RNA are presented, together with theoretical calculations of molecular couplings and molecular dynamics simulations. Backbone vibrations of DNA and RNA are established as sensitive noninvasive probes of the complex behavior of hydrated helices. The results reveal the femtosecond fluctuation dynamics of the water shell, the short-range character of Coulomb interactions, and the strength and fluctuation amplitudes of interfacial electric fields.Comment: To appear as Chapter 8 of Springer Series in Optical Sciences: Coherent Multidimensional Spectroscopy -- Editors: Cho, Minhaeng (Ed.), 201

Nanoparticles as Blood–Brain Barrier Permeable CNS Targeted Drug Delivery Systems

Research in the field of nano-neuroscience is becoming a promising future direction given the advantages presented by nanosystems for central nervous system (CNS) drug delivery. Since the blood–brain barrier (BBB) represents an invincible obstacle for the majority of drugs such as antineoplastic agents and a variety of psychoactive drugs such as neuropeptides, “smart” CNS drug delivery systems with high ability to deliver substances across the BBB are highly desired and will not only enable drugs to reach the CNS but also target specific areas of the CNS. Thus, injectable biodegradable nanoparticles have an important potential application in the treatment of a variety of neurological and psychiatric disorders. Therefore, in the following, we will highlight the requirement and importance of CNS drug delivery systems with particular emphasis on nano-scale systems. It is the objective of this article to offer a perspective on the complexity and challenges in fabrication of nanostructures, in vivo nano–bio interactions and also to highlight some of the most used nanosystems for drug delivery into the CNS

Assessment of Alzheimer’s Disease

Alzheimer’s disease (AD) is a devastating illness, affecting over 5.5 million adults in the United States and costing over 200 billion dollars annually. In this chapter, we describe the clinical manifestations of mild cognitive impairment (MCI), which constitutes a risk factor for AD and other neurodegenerative disorders, and describe the appropriate neuropsychological measures that tap the important cognitive domains that should be assessed in these conditions. We also highlight advances in the field related to the clinical diagnosis and biomarkers associated with AD, as well as novel measures that have shown increased sensitivity for early identification of preclinical AD. A summary of useful clinical tips and future directions in the field are addressed

Genome-Wide Association Study of Loneliness Demonstrates a Role for Common Variation.

Loneliness is a complex biological trait that has been associated with numerous negative health outcomes. The measurement and environmental determinants of loneliness are well understood, but its genetic basis is not. Previous studies have estimated the heritability of loneliness between 37 and 55% using twins and family-based approaches, and have explored the role of specific candidate genes. We used genotypic and phenotypic data from 10 760 individuals aged ⩾50 years that were collected by the Health and Retirement Study (HRS) to perform the first genome-wide association study of loneliness. No associations reached genome-wide significance (p>5 × 10-8). Furthermore, none of the previously published associations between variants within candidate genes (BDNF, OXTR, RORA, GRM8, CHRNA4, IL-1A, CRHR1, MTHFR, DRD2, APOE) and loneliness were replicated (p>0.05), despite our much larger sample size. We estimated the chip heritability of loneliness and examined coheritability between loneliness and several personality and psychiatric traits. Our estimates of chip heritability (14-27%) support a role for common genetic variation. We identified strong genetic correlations between loneliness, neuroticism, and a scale of 'depressive symptoms.' We also identified weaker evidence for coheritability with extraversion, schizophrenia, bipolar disorder, and major depressive disorder. We conclude that loneliness, as defined in this study, is a modestly heritable trait that has a highly polygenic genetic architecture. The coheritability between loneliness and neuroticism may reflect the role of negative affectivity that is common to both traits. Our results also reflect the value of studies that probe the common genetic basis of salutary social bonds and clinically defined psychiatric disorders