Cerebrospinal fluid concentrations of inflammatory markers in Parkinson's disease and atypical parkinsonian disorders

Inflammation has been implicated in the pathogenesis of Parkinson’s disease (PD). We here investigate levels of inflammatory biomarkers in cerebrospinal fluid (CSF) in PD and atypical parkinsonian disorders (APD) compared with neurologically healthy controls. We included 131 patients with PD and 27 PD with dementia (PDD), 24 with multiple system atrophy (MSA), 14 with progressive supranuclear palsy (PSP) and 50 controls, all part of the Swedish BioFINDER study. CSF was analyzed for CRP, SAA, IL-6, IL-8, YKL-40 and MCP-1 (CCL2) as well as α-synuclein (α-syn), tau, tau phosphorylated at Thr181 (P-tau), Aβ42 and NfL. In this exploratory study, we found higher levels of the inflammatory biomarker SAA in PDD and MSA compared with controls and PD and higher levels of CRP in PDD and MSA compared with PD. YKL-40 was lower in PD compared with controls. There were multiple positive correlations between the inflammatory markers, α-syn and markers of neuroaxonal injury (NfL and tau). In PD, higher levels of inflammatory biomarkers correlated with worse motor function and cognitive impairment. Thus, inflammatory biomarkers were increased in PDD and MSA. Furthermore, inflammatory biomarkers correlated with more severe disease regarding motor symptoms and cognitive impairment in PD, indicating an association between inflammation and more aggressive disease course. However, the results need confirmation in follow-up studies

Knock-Down of Core Proteins Regulating MicroRNA Biogenesis Has No Effect on Sensitivity of Lung Cancer Cells to Ionizing Radiation

Recent studies underline the important role of microRNAs (miRNA) in the development of lung cancer. The main regulators of miRNA biogenesis are the ribonucleases Drosha, Dicer and Ago2. Here the role of core proteins of miRNA biogenesis machinery in the response of human non-small and small cell lung carcinoma cell lines to treatment with ionizing radiation was assessed. We found that Drosha and Dicer were expressed at higher levels in radioresistant but not in sensitive cell lines. However, down-regulation of either Dicer or Drosha had no effect on the sensitivity of cells to irradiation. Elimination of components of the RNA-induced silencing complex Ago2 and Tudor staphylococcal nuclease also did not sensitize cells to the same treatment. Thus, modulation of miRNA biogenesis machinery is not sufficient to increase the radiosensitivity of lung tumors and other strategies are required to combat lung cancer

On complex-valued 2D eikonals. Part four: continuation past a caustic

Theories of monochromatic high-frequency electromagnetic fields have been designed by Felsen, Kravtsov, Ludwig and others with a view to portraying features that are ignored by geometrical optics. These theories have recourse to eikonals that encode information on both phase and amplitude -- in other words, are complex-valued. The following mathematical principle is ultimately behind the scenes: any geometric optical eikonal, which conventional rays engender in some light region, can be consistently continued in the shadow region beyond the relevant caustic, provided an alternative eikonal, endowed with a non-zero imaginary part, comes on stage. In the present paper we explore such a principle in dimension $2.$ We investigate a partial differential system that governs the real and the imaginary parts of complex-valued two-dimensional eikonals, and an initial value problem germane to it. In physical terms, the problem in hand amounts to detecting waves that rise beside, but on the dark side of, a given caustic. In mathematical terms, such a problem shows two main peculiarities: on the one hand, degeneracy near the initial curve; on the other hand, ill-posedness in the sense of Hadamard. We benefit from using a number of technical devices: hodograph transforms, artificial viscosity, and a suitable discretization. Approximate differentiation and a parody of the quasi-reversibility method are also involved. We offer an algorithm that restrains instability and produces effective approximate solutions.Comment: 48 pages, 15 figure

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field

Cerebrospinal fluid levels of neurogranin in Parkinsonian disorders

Background: CSF concentration of neurogranin has been suggested as a biomarker for synapse dysfunction. / Objectives: To investigate CSF neurogranin in parkinsonian disorders compared to controls and Alzheimer's disease and the possible correlations between neurogranin and cognitive and motor impairment. / Methods: We included 157 patients with PD, 29 with PD with dementia, 11 with dementia with Lewy bodies, 26 with MSA, 21 with PSP, 6 with corticobasal syndrome, 47 controls, and 124 with Alzheimer's disease. CSF neurogranin was measured using two enzyme‐linked immunosorbent assays; from EUROIMMUN and the University of Gothenburg. / Results: We found a strong correlation between CSF neurogranin‐EI and CSF neurogranin–University of Gothenburg (Rs = 0.890; P < 0.001). Neurogranin was decreased in PD, PD with dementia, MSA, and PSP compared to controls and Alzheimer's disease. Neurogranin did not correlate with motor or cognitive impairment, longitudinal decline, or progression to dementia in PD. / Conclusions: CSF neurogranin is decreased in parkinsonian disorders compared to controls, emphasizing the importance of synaptic dysfunction in these disorders

EEG vigilance modulates PCC between-network functional connectivity at rest

Introduction: Based on EEG acquisitions at resting state, it is possible to differentiate stages of wakefulness regulation [Olbrich et al., 2009]. A region that has a central role in supporting internally-directed cognition and showed both reduced neural activity and altered interaction with other brain regions in states of low arousal and awareness, is the posterior cingulate cortex (PCC) [Fox et al., 2005; Sämann et al., 2011]. It's dorsal and ventral subregions show heterogeneity in tuning functional brain states depending on environmental demands [Leech and Sharp, 2014; Liang et al., 2015]. To investigate the interplay between individual variations in tonic arousal level and network connectivity patterns, we analyzed how functional coupling between subregions of the PCC and their patterns of interconnection with major intrinsic connectivity networks (ICN) are modulated by vigilance. Methods: 16 neurotypical subjects (8 males, age: 28.1±7.4) underwent a simultaneous resting-state EEG-fMRI scan for ten minutes with closed eyes (Magdeburg, 3T Siemens Verio). EEG signals from 28 channels were preprocessed in EEGLab using FIR filter (0.5-125Hz), correction for gradient artifacts [Moosmann et al., 2009], carbon-wire based artifact correction [van der Meer et al., 2016], removal of additional artifact components by ICA, FIR filter (0.5-70Hz), downsampling to 500Hz and referenced to the FCz position with a ground electrode located at the AFz position. Using the VIGALL 2.0 algorithm, vigilance stages (high: A1, A2, A3, low: B2/3) in consecutive EEG segments (duration: 2.4s=1 TR) were classified [Sander et al., 2015]. FMRI images were preprocessed using slicetime correction, coregistration, segmentation, normalization, regression of signals from 6 motion regressors, white matter, CSF and a linear trend, bandpass filter (0.01-0.1 Hz), and scrubbing by interpolation in DPARSFA toolbox. To analyze functional coupling of PCC subregions, extracted timecourses of bilateral spherical seeds were correlated (dPCC: [±2, -34, 40], vPCC [±2, -58, 28], radius 6mm) [Leech et al., 2011]. To analyze the changes in between-network FC patterns, a network of 42 nodes placed in Default Mode Network (DMN), Dorsal Attention Network and Central Executive Network (CEN) [Spreng et al., 2013] and the four PCC nodes was created and the functional connectivity strength (FCS) of each PCC ROI to each ICN was calculated separately. EEG and fMRI metrics were correlated using Pearson correlation coefficient. Results: PCC subregions were functionally coupled, but dPCC and vPCC had strongest FCS to CEN and DMN, respectively. The percentage of subjects in low vigilance stages was constantly high and stable over time. Intra-PCC coupling was stronger if a subject spent more time in low vigilance stages (right hemisphere: p=0.026, r=-0.55, left hemisphere: p=0.019, r=-0.5) and if changes vigilance state were seldom (right hemisphere: p=0.027, r=-0.55, left hemisphere: p=0.035, r=-0.53). FCS between right dPCC and DMN was stronger, if the number of TR spent in high vigilance stages was low (p=0.038, r=-0.52) and if vigilance state changes were seldom (right PCC: p=0.02, r=-0.57, left PCC: p=0.049, r=-0.49). Conclusions: Existence of differential canonic FC to major ICN provides further evidence for functional heterogeneity of dPCC and vPCC. EEG-informed analysis of intra-PCC coupling revealed a modulating effect of vigilance in that coupling was strongest during low and stable vigilance. Vigilance predicted network interaction between dPCC and its non-canonical network DMN. Using combined EEG-fMRI data we showed that variations in arousal modulate functional coupling in the PCC and specifically interaction of the dorsal subregion to the DMN at rest