Chapter 6 - Cerebrospinal fluid in the dementias

Alzheimer disease, vascular dementia, dementia with Lewy bodies, and frontotemporal dementia are the most common central nervous system disorders that cause progressive neurocognitive dysfunction and ultimately dementia. A number of biomarkers for pathologies reflecting each condition have been developed. Here, we review these and give an overview of the current state of practice and research regarding cerebrospinal fluid biomarkers for these disorders. The chapter discusses both established (most of which are tau- and amyloid β-related) and upcoming biomarkers and details, wherever appropriate, clinical use and differential diagnostics aspects

BigLaw: Money and Meaning in the Modern Law Firm

The Great Recession intensified large law firms’ emphasis on financial performance, leading to claims that lawyers in these firms were now guided by business rather than professional values. Based on interviews with more than 250 partners in large firms, Mitt Regan and Lisa H. Rohrer suggest that the reality is much more complex. It is true that large firm hiring, promotion, compensation, and termination policies are more influenced by business considerations than ever before and that firms actively recruit profitable partners from other firms to replace those they regard as unproductive. At the same time, law firm partners continue to seek the non-financial rewards of being members of a distinct profession and are sensitive to whether their firms are committed to providing them. This book explores how lawyers are attempting to balance intensifying business demands and professional identity, and how firms play a crucial role in mediating efforts to navigate such tensions

Sources and distribution of NO(x) in the upper troposphere at northern midlatitudes

A simple quasi 2-D model is used to study the zonal distribution of NO(x). The model includes vertical transport in form of eddy diffusion and deep convection, zonal transport by a vertically uniform wind, and a simplified chemistry of NO, NO2 and HNO3. The NO(x) sources considered are surface emissions (mostly from the combustion of fossil fuel), lightning, aircraft emissions, and downward transport from the stratosphere. The model is applied to the latitude band of 40 deg N to 50 deg N during the month of June; the contributions to the zonal NO(x) distribution from the individual sources and transport processes are investigated. The model predicted NO(x) concentration in the upper troposphere is dominated by air lofted from the polluted planetary boundary layer over the large industrial areas of Eastern North America and Europe. Aircraft emissions are also important and contribute on average 30 percent. Stratospheric input is minor about 10 percent, less even than that by lightning. The model provides a clear indication of intercontinental transport of NO(x) and HNO3 in the upper troposphere. Comparison of the modelled NO profiles over the Western Atlantic with those measured during STRATOZ 3 in 1984 shows good agreement at all altitudes

A real-time semi-quantitative RT–PCR assay demonstrates that the pilE sequence dictates the frequency and characteristics of pilin antigenic variation in Neisseria gonorrhoeae

A semi-quantitative real-time RT–PCR assay was designed to measure gonococcal pilin antigenicvariation (SQ-PCR Av assay). This assay employs 17 hybridization probe sets that quantitate subpopulations of pilin transcripts carrying different silent pilin copy sequences and one set that detects total pilE transcript levels. Mixtures of a DNA standard carrying the silent copy being detected and a clone encoding the starting pilE sequence, which is the majority pilE template, provided amplification curves that closely matched the experimental data and allowed an analysis of the contribution of different silent pilin copies to variation. The SQ-PCR Av assay was verified using DNA sequence analysis to demonstrate that this methodology allowed an accurate analysis of pilin variation. Both assays showed that with a specific starting pilE sequence, only a subset of the silent pilin copies recombine into pilE at a detectable level, and that this limited subset was reproducibly detected in replicate cultures. When an isogenic pilE sequence variant was examined using both assays, a new subset of silent copy sequences were detected recombining into pilE and the overall frequency of variation was increased. Thus, the parental pilE sequence influences the frequency of variation and the repertoire of pilin variants produced

Spin-Correlation Coefficients and Phase-Shift Analysis for p+3^3He Elastic Scattering

Angular Distributions for the target spin-dependent observables A$_{0y}$, A$_{xx}$, and A$_{yy}$ have been measured using polarized proton beams at several energies between 2 and 6 MeV and a spin-exchange optical pumping polarized $^3$He target. These measurements have been included in a global phase-shift analysis following that of George and Knutson, who reported two best-fit phase-shift solutions to the previous global p+$^3$He elastic scattering database below 12 MeV. These new measurements, along with measurements of cross-section and beam-analyzing power made over a similar energy range by Fisher \textit{et al.}, allowed a single, unique solution to be obtained. The new measurements and phase-shifts are compared with theoretical calculations using realistic nucleon-nucleon potential models.Comment: Submitted to Phys. Rev.

Variable clinical phenotype in TBK1 mutations: case report of a novel mutation causing primary progressive aphasia and review of the literature

TBK1 mutations are a recently discovered cause of disorders in the frontotemporal dementia (FTD)-amyotrophic lateral sclerosis (ALS) spectrum. We describe a novel L683* mutation, predicted to cause a truncated protein and therefore be pathogenic, in a patient presenting with nonfluent variant primary progressive aphasia (PPA) at the age of 65. Her disease progressed over the following years, leading to her being mute and wheelchair bound seven years into her illness. Brain imaging showed asymmetrical left-sided predominant atrophy affecting the frontal, insular and temporal cortices as well as the striatum in particular. Review of the literature found 60 different nonsense, frameshift, deletion or splice site mutations, including the newly described mutation, with data on clinical diagnosis available in 110 people: 58% of the cases presented with an ALS syndrome, 16% with an FTD-ALS overlap, 19% with a cognitive presentation (including behavioural variant FTD (bvFTD) and PPA) and 4% with atypical parkinsonism. Age at onset (AAO) data was available in 75 people: mean (standard deviation) AAO was 57.5 (10.3) in those with ALS, which was significantly younger than those with a cognitive presentation (AAO = 65.1 (10.5), p = 0.008), or atypical parkinsonism (AAO = 68.3 (8.7), p = 0.021), with a trend compared with the FTD-ALS group (AAO = 61.9 (7.0), p=0.065); there was no significant difference in AAO between the other groups. In conclusion, clinical syndromes across the whole FTD-ALS-atypical parkinsonism spectrum have been reported in conjunction with mutations in TBK1. It is therefore important to include TBK1 on future gene panels for each of these disorders, and to suspect such mutations particularly when there are multiple different phenotypes in the same family

Differential chemokine alteration in the variants of primary progressive aphasia-a role for neuroinflammation

BACKGROUND: The primary progressive aphasias (PPA) represent a group of usually sporadic neurodegenerative disorders with three main variants: the nonfluent or agrammatic variant (nfvPPA), the semantic variant (svPPA), and the logopenic variant (lvPPA). They are usually associated with a specific underlying pathology: nfvPPA with a primary tauopathy, svPPA with a TDP-43 proteinopathy, and lvPPA with underlying Alzheimer's disease (AD). Little is known about their cause or pathophysiology, but prior studies in both AD and svPPA have suggested a role for neuroinflammation. In this study, we set out to investigate the role of chemokines across the PPA spectrum, with a primary focus on central changes in cerebrospinal fluid (CSF) METHODS: Thirty-six participants with sporadic PPA (11 svPPA, 13 nfvPPA, and 12 lvPPA) as well as 19 healthy controls were recruited to the study and donated CSF and plasma samples. All patients with lvPPA had a tau/Aβ42 biomarker profile consistent with AD, whilst this was normal in the other PPA groups and controls. We assessed twenty chemokines in CSF and plasma using Proximity Extension Assay technology: CCL2 (MCP-1), CCL3 (MIP-1a), CCL4 (MIP-1β), CCL7 (MCP-3), CCL8 (MCP-2), CCL11 (eotaxin), CCL13 (MCP-4), CCL19, CCL20, CCL23, CCL25, CCL28, CX3CL1 (fractalkine), CXCL1, CXCL5, CXCL6, CXCL8 (IL-8), CXCL9, CXCL10, and CXCL11. RESULTS: In CSF, CCL19 and CXCL6 were decreased in both svPPA and nfvPPA compared with controls whilst CXCL5 was decreased in the nfvPPA group with a borderline significant decrease in the svPPA group. In contrast, CCL2, CCL3 and CX3CL1 were increased in lvPPA compared with controls and nfvPPA (and greater than svPPA for CX3CL1). CXCL1 was also increased in lvPPA compared with nfvPPA but not the other groups. CX3CL1 was significantly correlated with CSF total tau concentrations in the controls and each of the PPA groups. Fewer significant differences were seen between groups in plasma, although in general, results were in the opposite direction to CSF, i.e. decreased in lvPPA compared with controls (CCL3 and CCL19), and increased in svPPA (CCL8) and nfvPPA (CCL13). CONCLUSION: Differential alteration of chemokines across the PPA variants is seen in both CSF and plasma. Importantly, these results suggest a role for neuroinflammation in these poorly understood sporadic disorders, and therefore also a potential future therapeutic target