scholarly journals Origins of atrophy in Parkinson linked to early onset and local transcription patterns

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Pedro D Maia ◽  
Sneha Pandya ◽  
Benjamin Freeze ◽  
Justin Torok ◽  
Ajay Gupta ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
Age Of Onset ◽  
Brain Regions ◽  
Initiation Site ◽  
Clinical Value ◽  
Screening Strategies ◽  
The Individual ◽  
Immune Related Genes ◽  
Post Hoc ◽  
Penalized Optimization

Abstract There is enormous clinical value in inferring the brain regions initially atrophied in Parkinson disease for individual patients and understanding its relationship with clinical and genetic risk factors. The aim of this study is to leverage a new seed-inference algorithm demonstrated for Alzheimer’s disease to the Parkinsonian context and to cluster patients in meaningful subgroups based on these incipient atrophy patterns. Instead of testing brain regions separately as the likely initiation site for each patient, we solve an L1-penalized optimization problem that can return a more predictive heterogeneous, multi-locus seed patterns. A cluster analysis of the individual seed patterns reveals two distinct subgroups (S1 versus S2). The S1 subgroup is characterized by the involvement of the brainstem and ventral nuclei, and S2 by cortex and striatum. Post hoc analysis in features not included in the clustering shows significant differences between subgroups regarding age of onset and local transcriptional patterns of Parkinson-related genes. Top genes associated with regional microglial abundance are strongly associated with subgroup S1 but not with S2. Our results suggest two distinct aetiological mechanisms operative in Parkinson disease. The interplay between immune-related genes, lysosomal genes, microglial abundance and atrophy initiation sites may explain why the age of onset for patients in S1 is on average 4.5 years later than for those in S2. We highlight and compare the most prominently affected brain regions for both subgroups. Altogether, our findings may improve current screening strategies for early Parkinson onsetters.

Error Management in Audit Firms: Error Climate, Type, and Originator

2013 ◽  
Vol 89 (1) ◽  
pp. 303-330 ◽  
Author(s):  
Anna Gold ◽  
Ulfert Gronewold ◽  
Steven E. Salterio
Keyword(s):  
Impression Management ◽  
Data Availability ◽  
Error Management ◽  
Organizational Life ◽  
Climate Type ◽  
Error Type ◽  
Audit Firms ◽  
The Individual ◽  
Post Hoc ◽  
Willingness To Report

ABSTRACT This paper examines how the treatment of audit staff who discover errors in audit files by superiors affects their willingness to report these errors. The way staff are treated by superiors is labelled as the audit office error management climate. In a “blame-oriented” climate errors are not tolerated and those committing errors are punished. In contrast, an “open” climate characterizes error commitment as a normal, albeit unfortunate aspect of organizational life that offers opportunities for learning without sanctions on the originator. We examine error management climate in the context of audit-specific factors that might affect the decision to report errors: audit error type (conceptual or mechanical) and who committed the error (the individual who discovered it or a peer). An open climate results in an increase in the reporting of mechanical (but not conceptual) errors and all peer errors versus a blame climate. Post hoc findings suggest that one obstacle to reporting conceptual errors stems from an auditor's own impression management concerns. We discuss how auditing standards and regulatory inspections may impact audit firm error management climates. Data Availability: Experimental data are available from the second author subject to data confidentiality restrictions issued by the participating firms.

Visual Cortex Alterations in Early and Late Blind Subjects During Tactile Perception

Perception ◽  
2021 ◽  
Vol 50 (3) ◽  
pp. 249-265
Author(s):  
A. Ankeeta ◽  
S. Senthil Kumaran ◽  
Rohit Saxena ◽  
Sada N. Dwivedi ◽  
Naranamangalam R. Jagannathan
Keyword(s):  
Visual Cortex ◽  
Children And Adolescents ◽  
Age Of Onset ◽  
Human Subjects ◽  
Functional Results ◽  
Blood Oxygen Level Dependent ◽  
Tactile Perception ◽  
Blood Oxygen Level ◽  
Sensory Motor ◽  
Post Hoc

Involvement of visual cortex varies during tactile perception tasks in early blind (EB) and late blind (LB) human subjects. This study explored differences in sensory motor networks associated with tactile task in EB and LB subjects and between children and adolescents. A total of 40 EB subjects, 40 LB subjects, and 30 sighted controls were recruited in two subgroups: children (6–12 years) and adolescents (13–19 years). Data were acquired using a 3T MR scanner. Analyses of blood oxygen level dependent (BOLD), functional connectivity (FC), correlation, and post hoc test for multiple comparisons were carried out. Difference in BOLD activity was observed in EB and LB groups in visual cortex during tactile perception, with increased FC of visual with dorsal attention and sensory motor networks in EB. EB adolescents exhibited increased connectivity with default mode and salience networks when compared with LB. Functional results correlated with duration of training, suggestive of better performance in EB. Alteration in sensory and visual networks in EB and LB correlated with duration of tactile training. Age of onset of blindness has an effect in cross-modal reorganization of visual cortex in EB and multimodal in LB in children and adolescents.

scholarly journals Defining early changes in Alzheimer’s disease from RNA sequencing of brain regions differentially affected by pathology

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Boris Guennewig ◽  
Julia Lim ◽  
Lee Marshall ◽  
Andrew N. McCorkindale ◽  
Patrick J. Paasila ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rna Sequencing ◽  
Neuronal Loss ◽  
Brain Regions ◽  
Post Mortem ◽  
Tau Pathology ◽  
Membrane Spanning ◽  
Immune Related Genes ◽  
Vesicle Secretion

AbstractTau pathology in Alzheimer’s disease (AD) spreads in a predictable pattern that corresponds with disease symptoms and severity. At post-mortem there are cortical regions that range from mildly to severely affected by tau pathology and neuronal loss. A comparison of the molecular signatures of these differentially affected areas within cases and between cases and controls may allow the temporal modelling of disease progression. Here we used RNA sequencing to explore differential gene expression in the mildly affected primary visual cortex and moderately affected precuneus of ten age-, gender- and RNA quality-matched post-mortem brains from AD patients and healthy controls. The two regions in AD cases had similar transcriptomic signatures but there were broader abnormalities in the precuneus consistent with the greater tau load. Both regions were characterised by upregulation of immune-related genes such as those encoding triggering receptor expressed on myeloid cells 2 and membrane spanning 4-domains A6A and milder changes in insulin/IGF1 signalling. The precuneus in AD was also characterised by changes in vesicle secretion and downregulation of the interneuronal subtype marker, somatostatin. The ‘early’ AD transcriptome is characterised by perturbations in synaptic vesicle secretion on a background of neuroimmune dysfunction. In particular, the synaptic deficits that characterise AD may begin with the somatostatin division of inhibitory neurotransmission.

scholarly journals Serial Analysis of Antimitochondrial Antibody in Patients with Primary Biliary Cirrhosis

2004 ◽  
Vol 11 (2) ◽  
pp. 129-133 ◽  
Author(s):  
Gordon D. Benson ◽  
Kentaro Kikuchi ◽  
Hiroshi Miyakawa ◽  
Atsushi Tanaka ◽  
Mitchell R. Watnik ◽  
...  
Keyword(s):  
Primary Biliary Cirrhosis ◽  
Age Of Onset ◽  
Biliary Cirrhosis ◽  
Younger Patients ◽  
Serologic Marker ◽  
Dependent Change ◽  
Time Dependent Change ◽  
Specific Igg ◽  
The Individual

Antimitochondrial antibodies (AMAs) are the classic serologic marker in primary biliary cirrhosis (PBC). However, there have been only limited attempts to study changes in titer or isotype analysis of such AMAs in patients followed for long periods of timeWe took advantage of stored sera from well-characterized patients with PBC followed for a period of 7-28 years (mean duration of 13.5 years). Immunoblot and enzyme-linked immunosorbant assays were performed against PDC-E2, BCOADC-E2 and OGDC-E2 as well as isotype analysis of antigen-specific IgG, IgA and IgM antibodies against each of these mitochondrial autoantigens. Sera were analyzed for total IgG, IgA and IgM by radial immunodiffusion. The sera titer of AMAs was significantly higher in younger patients with PBC. Indeed, age of onset of clinical PBC was a significant predictor for the highest values of sera AMAs. In contrast, the AMA titer did not significantly change over time in this prolonged longitudinal study. The total sera levels of the individual immunoglobulins did not show a time-dependent change, when based on age of onset of the disease. Higher titers of AMAs were noted in the younger patients. Furthermore, despite this long follow-up, there was no evidence for a significant change in AMA levels; also, levels were not influenced by drug therapy used during the period of observation.

scholarly journals Monitoring changes in the shape of the spine in children with postural disorders

2021 ◽  
Author(s):  
Arkadiusz Żurawski ◽  
Zbigniew Śliwiński ◽  
Grażyna Nowak Starz ◽  
Wojciech Kiebzak (Kiebzak)
Keyword(s):  
Three Dimensional ◽  
Control Group ◽  
Spine Deformity ◽  
Study Group ◽  
Lateral Deviation ◽  
Method Of Measurement ◽  
The Individual ◽  
Post Hoc ◽  
And Control ◽  
Postural Disorders

Abstract BackgroundDue to numerous complications of an abnormal shape of the spine, it is extremely important to systematically monitor its shape. Precise and routine method of measurement enables comparison of the scores obtained over time and possible early intervention in order to avoid complications.The aim of the work is to present the pattern for monitoring changes in the shape of the spine in children with postural deformities.MethodsThe study group (n = 211) consisted of the patients with diagnosed shape of the spine deformity, who underwent a four-month therapy, supervised by a physiotherapist. The control group (n = 101) were the children with no shape of spine deformity.The children in the study group underwent a three-dimensional computer analysis of the shape of the spine. The DIERS test was performed in both groups (study and control). In the study group it was performed four times. It involved the measurement of seven parameters enabling a complete assessment of body posture.ResultsStatistically significant scores of the Friedman test for imbalance, pelvic tilt, kyphosis angle, lordosis angle, and lateral deviation were observed. Therefore, a series of post-hoc analyzes were performed using Dunn-Bonferroni tests. It was observed that changes in individual parameters analyzed in the authors' study come up at a different pace.ConclusionsDetailed monitoring of the parameters describing the position of the spine makes it possible to control the course of the treatment process of patients with disorders of the position of the spine. The dynamics of changes taking place within the spine position varies for the individual parameters analyzed.

scholarly journals Somatic mutations in Parkinson disease are enriched in synaptic and neuronal processes

2020 ◽  
Author(s):  
Irene Lobon ◽  
Manuel Solis-Moruno ◽  
David Juan ◽  
Ashraf Muhaisen ◽  
Federico Abascal ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
Somatic Mutations ◽  
Amplicon Sequencing ◽  
Brain Regions ◽  
Single Nucleotide Variants ◽  
Validation Rate ◽  
Synaptic Functions ◽  
Whole Exome ◽  
Neuronal Processes

The role of somatic mutations in complex diseases, including neurodevelopmental and neurodegenerative disorders, is becoming increasingly clear. To explore their relevance in sporadic Parkinson disease, we performed whole-exome sequencing in blood and four brain regions of ten patients. We identified 59 candidate somatic single nucleotide variants (sSNVs) through sensitive calling and extensive filtering. We validated 27 of them with amplicon-based deep sequencing, with a 70% validation rate for the highest-confidence variants. Most of the sSNVs were exclusively called in blood but were also found in the brain tissues with the ultra-deep amplicon sequencing, demonstrating the strength of multi-tissue sampling designs. We could confirm between 0 and 6 sSNVs per patient and generally those with a shorter lifespan carried more variants. Remarkably, the validated sSNVs are enriched in genes with synaptic functions that are co-expressed with genes previously associated with Parkinson disease.

scholarly journals Identification and Research of Adhd and Healthy Controls using Fmri

2019 ◽  
Vol 8 (6S) ◽  
pp. 370-372
Keyword(s):  
Brain Regions ◽  
Healthy Controls ◽  
Hyperactivity Disorder ◽  
Network Activation ◽  
Healthy Control ◽  
Temporal And Spatial ◽  
The Individual ◽  
The Brain ◽  
Coronal View

Analyzing the brain regions for different activations corresponding to the activation input for an experimental setup of task functional MRI or a resting state functional Magnetic Resonance Imaging(fMRI) for a diagnosed or healthy control is a challenging issue as the processing data is voluminous 4D data with nearly 1,51,552 voxels for a single volume of 261 scans fMRI. The data considered for analysis consists of 10 healthy controls and 10 Attention Deficit Hyperactivity Disorder(ADHD) fMRI. The workflow starts with preprocessing the individual scan for realignment, coregistration and Normalisation to Montreal Neurological Institute (MNI) space. Single site scan visit consists of 64x64x37 voxels. Seventy independent components are obtained from processed data by data reduction, Independent Component Analysis (ICA) calculation, Back reconstruction and Component Calibration. ICA performs satisfactorily well on temporal and spatial localization. Visual medial network activation is pronounced in ADHD Controls than in healthy people. Sagittal, Axial and Coronal view of ADHD controls is obtained as component number 42.The analysis is further used for the automatic classification of healthy controls and ADHD people.

scholarly journals Genetic analyses of SERPINA5 in Alzheimer’s disease

2021 ◽  
Author(s):  
Billie J. Matchett ◽  
Sarah J. Lincoln ◽  
Matt Baker ◽  
Nikoleta Tamvaka ◽  
Janisse Cabrera-Rodriguez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Duration ◽  
Age Of Onset ◽  
Positive Family History ◽  
Neuronal Loss ◽  
Missense Variant ◽  
Brain Regions ◽  
Allelic Frequency ◽  
Genomic Databases

Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disease that is the most common cause of dementia. Our previous studies have shown that increased expression of the SERPINA5 gene is associated with hippocampal vulnerability in AD, and that the SERPINA5 protein binds to tau and co-localizes within neurofibrillary tangles. To determine if genetic variants in the SERPINA5 gene may be contributing to this phenotype, we sequenced 103 autopsy-confirmed young-onset AD cases with a positive family history of cognitive decline. We observed one individual with a rare missense variant (rs140138746) in the SERPINA5 gene, resulting in an amino acid change (p.E228Q). We screened a further 1170 neuropathologically diagnosed AD cases and identified an additional 5 carriers of this variant, resulting in an allelic frequency of 0.002141 within our AD validation cohort, which was comparable to online genomic databases. Although not significant, SERPINA5 p.E228Q variant carriers were found to be younger at age of onset and age of death than non-carriers. SERPINA5 p.E228Q variant carriers had a longer disease duration than non-carriers, which approached significance. To further elucidate possible neuropathologic contributions of the SERPINA5 p.E228Q variant, we carried out descriptive neuropathologic burden analysis on a variant carrier that was matched to a non-carrier for age, sex, disease duration, Braak tangle stage, TDP-43 positive status, and who possessed an APOE ε4 risk allele. Interestingly, SERPINA5 burden was lower in the SERPINA5 p.E228Q carrier than the non-carrier in 9 corticolimbic brain regions studied, which exaggerated the tau:SERPINA5 immunohistochemical ratio. The SERPINA5 p.E228Q carrier was observed to have more severe neuronal loss in several brain regions compared to the non-carrier. Together, we cautiously interpret these findings to suggest that the SERPINA5 p.E228Q variant may stall tangle maturity and slow AD disease progression, thus prolonging disease duration in these individuals.

scholarly journals Resting-state brain activity can predict target-independent aptitude in fMRI-neurofeedback training

2021 ◽  
Author(s):  
Takashi Nakano ◽  
Masahiro Takamura ◽  
Haruki Nishimura ◽  
Maro Machizawa ◽  
Naho Ichikawa ◽  
...  
Keyword(s):  
Resting State ◽  
Brain Connectivity ◽  
Brain Activity ◽  
Resting State Fmri ◽  
Brain Regions ◽  
Posterior Cingulate Cortex ◽  
Fmri Data ◽  
Independent Test ◽  
The Individual ◽  
The Brain

AbstractNeurofeedback (NF) aptitude, which refers to an individual’s ability to change its brain activity through NF training, has been reported to vary significantly from person to person. The prediction of individual NF aptitudes is critical in clinical NF applications. In the present study, we extracted the resting-state functional brain connectivity (FC) markers of NF aptitude independent of NF-targeting brain regions. We combined the data in fMRI-NF studies targeting four different brain regions at two independent sites (obtained from 59 healthy adults and six patients with major depressive disorder) to collect the resting-state fMRI data associated with aptitude scores in subsequent fMRI-NF training. We then trained the regression models to predict the individual NF aptitude scores from the resting-state fMRI data using a discovery dataset from one site and identified six resting-state FCs that predicted NF aptitude. Next we validated the prediction model using independent test data from another site. The result showed that the posterior cingulate cortex was the functional hub among the brain regions and formed predictive resting-state FCs, suggesting NF aptitude may be involved in the attentional mode-orientation modulation system’s characteristics in task-free resting-state brain activity.

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