Fully automated deep learning-based localization and segmentation of the locus coeruleus in aging and Parkinson's disease using neuromelanin-sensitive MRI

Purpose: Development and performance measurement of a fully automated pipeline that localizes and segments the locus coeruleus in so-called neuromelanin-sensitive magnetic resonance imaging data for the derivation of quantitative biomarkers of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Methods: We propose a pipeline composed of several 3D-Unet-based convolutional neural networks for iterative multi-scale localization and multi-rater segmentation and non-deep learning-based components for automated biomarker extraction. We trained on the healthy aging cohort and did not carry out any adaption or fine-tuning prior to the application to Parkinson’s disease subjects. Results: The localization and segmentation pipeline demonstrated sufficient performance as measured by Euclidean distance (on average around 1.3mm on healthy aging subjects and 2.2mm in Parkinson’s disease subjects) and Dice similarity coefficient (overall around 71% on healthy aging subjects and 60% for subjects with Parkinson’s disease) as well as promising agreement with respect to contrast ratios in terms of intraclass correlation coefficient of ≥0.80 for healthy aging subjects compared to a manual segmentation procedure. Lower values (≥0.48) for Parkinson’s disease subjects indicate the need for further investigation and tests before the application to clinical samples. Conclusion: These promising results suggest the usability of the proposed algorithm for data of healthy aging subjects and pave the way for further investigations using this approach on different clinical datasets to validate its practical usability more conclusively

The whole-brain pattern of magnetic susceptibility perturbations in Parkinson's disease

Although iron-mediated oxidative stress has been proposed as a potential pathomechanism in Parkinson's disease, the global distribution of iron accumulation in Parkinson's disease has not yet been elucidated. This study used a new magnetic resonance imaging contrast, quantitative susceptibility mapping, and state-of-the-art methods to map for the first time the whole-brain landscape of magnetostatic alterations as a surrogate for iron level changes in n = 25 patients with idiopathic Parkinson's disease versus n = 50 matched controls. In addition to whole-brain analysis, a regional study including sub-segmentation of the substantia nigra into dorsal and ventral regions and qualitative assessment of susceptibility maps in single subjects were also performed. The most remarkable basal ganglia effect was an apparent magnetic susceptibility increase-consistent with iron deposition-in the dorsal substantia nigra, though an effect was also observed in ventral regions. Increased bulk susceptibility, additionally, was detected in rostral pontine areas and in a cortical pattern tightly concordant with known Parkinson's disease distributions of α-synuclein pathology. In contrast, the normally iron-rich cerebellar dentate nucleus returned a susceptibility reduction suggesting decreased iron content. These results are in agreement with previous post-mortem studies in which iron content was evaluated in specific regions of interest; however, extensive neocortical and cerebellar changes constitute a far more complex pattern of iron dysregulation than was anticipated. Such findings also stand in stark contrast to the lack of statistically significant group change using conventional magnetic resonance imaging methods namely voxel-based morphometry, cortical thickness analysis, subcortical volumetry and tract-based diffusion tensor analysis; confirming the potential of whole-brain quantitative susceptibility mapping as an in vivo biomarker in Parkinson's disease

Noradrenergic-dependent functions are associated with age-related locus coeruleus signal intensity differences.

The locus coeruleus (LC), the origin of noradrenergic modulation of cognitive and behavioral function, may play an important role healthy ageing and in neurodegenerative conditions. We investigated the functional significance of age-related differences in mean normalized LC signal intensity values (LC-CR) in magnetization-transfer (MT) images from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) cohort - an open-access, population-based dataset. Using structural equation modelling, we tested the pre-registered hypothesis that putatively noradrenergic (NA)-dependent functions would be more strongly associated with LC-CR in older versus younger adults. A unidimensional model (within which LC-CR related to a single factor representing all cognitive and behavioral measures) was a better fit with the data than the a priori two-factor model (within which LC-CR related to separate NA-dependent and NA-independent factors). Our findings support the concept that age-related reduction of LC structural integrity is associated with impaired cognitive and behavioral function

Selective release of muscle-specific, extracellular microRNAs during myogenic differentiation

MyomiRs are muscle-specific microRNAs (miRNAs) that regulate myoblast proliferation and differentiation. Extracellular myomiRs (ex-myomiRs) are highly enriched in the serum of Duchenne Muscular Dystrophy (DMD) patients and dystrophic mouse models and consequently have potential as disease biomarkers. The biological significance of miRNAs present in the extracellular space is not currently well understood. Here we demonstrate that ex-myomiR levels are elevated in perinatal muscle development, during the regenerative phase that follows exercise-induced myoinjury, and concomitant with myoblast differentiation in culture. Whereas ex-myomiRs are progressively and specifically released by differentiating human primary myoblasts and C2C12 cultures, chemical induction of apoptosis in C2C12 cells results in indiscriminate miRNA release. The selective release of myomiRs as a consequence of cellular differentiation argues against the idea that they are solely waste products of muscle breakdown, and suggests they may serve a biological function in specific physiological contexts. Ex-myomiRs in culture supernatant and serum are predominantly non-vesicular, and their release is independent of ceramide-mediated vesicle secretion. Furthermore, ex-myomiRs levels are reduced in aged dystrophic mice, likely as a consequence of chronic muscle wasting. In conclusion, we show that myomiR release accompanies periods of myogenic differentiation in cell culture and in vivo. Serum myomiR abundance is therefore a function of the regenerative/degenerative status of the muscle, overall muscle mass, and tissue expression levels. These findings have implications for the use of ex-myomiRs as biomarkers for DMD disease progression and monitoring response to therapy

The Role of the Striatum in Learning to Orthogonalize CD Action and Valence: A Combined PET and 7 T MRI Aging Study

Pavlovian biases influence instrumental learning by coupling reward seeking with action invigoration and punishment avoidance with action suppression. Using a probabilistic go/no-go task designed to orthogonalize action (go/no-go) and valence (reward/punishment), recent studies have shown that the interaction between the two is dependent on the striatum and its key neuromodulator dopamine. Using this task, we sought to identify how structural and neuromodulatory age-related differences in the striatum may influence Pavlovian biases and instrumental learning in 25 young and 31 older adults. Computational modeling revealed a significant age-related reduction in reward and punishment sensitivity and marked (albeit not significant) reduction in learning rate and lapse rate (irreducible noise). Voxel-based morphometry analysis using 7 Tesla MRI images showed that individual differences in learning rate in older adults were related to the volume of the caudate nucleus. In contrast, dopamine synthesis capacity in the dorsal striatum, assessed using [18F]-DOPA positron emission tomography in 22 of these older adults, was not associated with learning performance and did not moderate the relationship between caudate volume and learning rate. This multiparametric approach suggests that age-related differences in striatal volume may influence learning proficiency in old age

Learning in anticipation of reward and punishment: perspectives across the human lifespan

Learning to act to receive reward and to withhold to avoid punishment has been found to be easier than learning the opposite contingencies in young adults. To what extent this type of behavioral adaptation might develop during childhood and adolescence and differ during aging remains unclear. We therefore tested 247 healthy individuals across the human life span (7-80 years) with an orthogonalized valenced go/no-go learning task. Computational modeling revealed that peak performance in young adults was attributable to greater sensitivity to both reward and punishment. However, in children and adolescents, we observed an increased bias toward action but not reward sensitivity. By contrast, reduced learning in midlife and older adults was accompanied by decreased reward sensitivity and especially punishment sensitivity along with an age-related increase in the Pavlovian bias. These findings reveal distinct motivation-dependent learning capabilities across the human life span, which cannot be probed using conventional go/reward no-go/punishment style paradigms that have important implications in lifelong education

Locus coeruleus MRI contrast is reduced in Alzheimer's disease dementia and correlates with CSF Aβ levels

Introduction: This study aimed to assess how interindividual differences in locus coeruleus (LC) magnetic resonance imaging (MRI) contrast relate to cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD). Methods: LC MRI contrast was quantified in 73 individuals from the DZNE Longitudinal Cognitive Impairment and Dementia Study (DELCODE) study comprising 25 healthy elderly adults and 21 individuals with subjective cognitive decline, 16 with mild cognitive impairment, and 11 participants with AD dementia using 3D T 1 -weighted fast low-angle shot (FLASH) imaging (0.75 mm isotropic resolution). Bootstrapped Pearson's correlations between LC contrast, CSF amyloid, and tau were performed in 44 individuals with CSF biomarker status. Results: A significant regional decrease in LC MRI contrast was observed in patients with AD dementia but not mild cognitive impairment and subjective cognitive decline compared with healthy controls. A negative association between LC MRI contrast and levels of CSF amyloid but not with CSF tau was found. Discussion: These results provide first evidence for a direct association between LC MRI contrast using in vivo T 1 -weighted FLASH imaging and AD pathology

Mindfulness-based interventions in epilepsy: a systematic review

Mindfulness based interventions (MBIs) are increasingly used to help patients cope with physical and mental long-term conditions (LTCs). Epilepsy is associated with a range of mental and physical comorbidities that have a detrimental effect on quality of life (QOL), but it is not clear whether MBIs can help. We systematically reviewed the literature to determine the effectiveness of MBIs in people with epilepsy. Medline, Cochrane Central Register of Controlled Trials, EMBASE, CINAHL, Allied and Complimentary Medicine Database, and PsychInfo were searched in March 2016. These databases were searched using a combination of subject headings where available and keywords in the title and abstracts. We also searched the reference lists of related reviews. Study quality was assessed using the Cochrane Collaboration risk of bias tool. Three randomised controlled trials (RCTs) with a total of 231 participants were included. The interventions were tested in the USA (n = 171) and China (Hong Kong) (n = 60). Significant improvements were reported in depression symptoms, quality of life, anxiety, and depression knowledge and skills. Two of the included studies were assessed as being at unclear/high risk of bias - with randomisation and allocation procedures, as well as adverse events and reasons for drop-outs poorly reported. There was no reporting on intervention costs/benefits or how they affected health service utilisation. This systematic review found limited evidence for the effectiveness of MBIs in epilepsy, however preliminary evidence suggests it may lead to some improvement in anxiety, depression and quality of life. Further trials with larger sample sizes, active control groups and longer follow-ups are needed before the evidence for MBIs in epilepsy can be conclusively determined

Why the South Pacific Convergence Zone is diagonal

During austral summer, the majority of precipitation over the Pacific Ocean is concentrated in the South Pacific Convergence Zone (SPCZ). The surface boundary conditions required to support the diagonally (northwest-southeast) oriented SPCZ are determined through a series of experiments with an atmospheric general circulation model. Continental configuration and orography do not have a significant influence on SPCZ orientation and strength. The key necessary boundary condition is the zonally asymmetric component of the sea surface temperature (SST) distribution. This leads to a strong subtropical anticyclone over the southeast Pacific that, on its western flank, transports warm moist air from the equator into the SPCZ region. This moisture then intensifies (diagonal) bands of convection that are initiated by regions of ascent and reduced static stability ahead of the cyclonic vorticity in Rossby waves that are refracted toward the westerly duct over the equatorial Pacific. The climatological SPCZ is comprised of the superposition of these diagonal bands of convection. When the zonally asymmetric SST component is reduced or removed, the subtropical anticyclone and its associated moisture source is weakened. Despite the presence of Rossby waves, significant moist convection is no longer triggered; the SPCZ disappears. The diagonal SPCZ is robust to large changes (up to +/-6 degC) in absolute SST (i.e. where the SST asymmetry is preserved). Extreme cooling (change less than -6 degC) results in a weaker and more zonal SPCZ, due to decreasing atmospheric temperature, moisture content and convective available potential energy