Abstract Multifactorial mechanisms underlying late-onset Alzheimer’s disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD–abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system’s integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions.
Significance Here we report a fundamental and previously unknown role for the receptor tyrosine kinase AXL as a direct hypoxia-inducible transcription factor target driving the aggressive phenotype in renal clear cell carcinoma through the regulation of the SRC proto-oncogene nonreceptor tyrosine kinase and the MET proto-oncogene receptor tyrosine kinase. Of therapeutic relevance, we demonstrate that inactivation of growth arrest-specific 6 (GAS6)/AXL signaling using a soluble AXL decoy receptor reversed the invasive and metastatic phenotype of clear cell renal cell carcinoma (ccRCC) cells. Furthermore, we define a pathway by which GAS6/AXL signaling utilizes lateral activation of MET through SRC to maximize cellular invasion. Our data provide an alternative model for SRC and MET activation by GAS6 in ccRCC and identify AXL as a therapeutic target driving the aggressive phenotype in renal clear cell carcinoma.
To estimate a regional progression pattern of amyloid deposition from cross-sectional amyloid-sensitive PET data and evaluate its potential for in vivo staging of an individual's amyloid pathology.
Abstract Background Pathogenic mutations in the progranulin gene ( GRN ) are a key cause of frontotemporal dementia (FTD), inducing a reduced biofluid concentration of the progranulin protein (PGRN). PGRN is a cysteine‐rich glycoprotein with essential roles in inflammation and lysosomal function, made up of 7 granulin peptides and 1 paragranulin. The role of these peptides is unclear, but existing data suggests they may have contradictory roles to full‐length PGRN. With the development of numerous clinical trials aiming to treat progranulin‐associated FTD (FTD‐GRN) by increasing full‐length PGRN, it is important to establish effective outcome measures to assess treatment success and further our understanding of PGRN’s biology. Here, we aimed to develop an assay to quantify granulin peptides in cerebrospinal fluid (CSF) and determine whether they contribute to the pathology of FTD‐GRN. Method Based on previously published explorative data of endogenous CSF peptides, 12 peptides spanning the progranulin sequence, were selected for the development of targeted assays using a quadrupole Orbitrap hybrid mass spectrometer (Fusion Tribrid, Thermo). An analytical protocol was optimised involving reduction, alkylation, molecular weight cut‐off filtration and solid phase extraction, and using isotope labelled heavy standards for quantification. Additionally, tandem mass tag (TMT) proteomics was used to analyse tryptic peptides spanning granulin and paragranulin sequence regions in 248 CSF samples from the Genetic FTD initiative (GENFI) including 56 GRN mutation carriers and 76 mutation‐negative controls. Result Preliminary results reveal the presence of three endogenous peptides in CSF, which based on sequence matching, likely represent granulin 6 and 7 alongside the paragranulin peptide. TMT results showed significantly reduced relative peptide intensity across the granulin regions in GRN carriers CSF compared to controls (p<0.0001), but no significant difference in the paragranulin region (p>0.33). Conclusion These findings indicate that two granulins and paragranulin are quantifiable in CSF and may have key roles in progranulin biology and potentially FTD pathology. This is supported by TMT results of differential CSF paragranulin levels compared to granulins. Continuing work will quantify CSF granulin concentrations in the GENFI cohort to assess whether these peptides have key roles in FTD‐GRN’s underlying biology and as potential outcome measures in trials.
Background Current clinical rating scales in frontotemporal dementia (FTD) often do not incorporate neuropsychiatric features and may therefore inadequately measure disease stage. Methods 832 participants from the Genetic FTD Initiative (GENFI) were recruited: 522 mutation carriers and 310 mutation-negative controls. The standardised GENFI clinical questionnaire assessed the frequency and severity of 14 neuropsychiatric symptoms: visual, auditory, and tactile hallucinations, delusions, depression, anxiety, irritability/lability, agitation/aggression, euphoria/elation, aberrant motor behaviour, hypersexuality, hyperreligiosity, impaired sleep, and altered sense of humour. A principal component analysis (PCA) was performed to identify key groupings of neuropsychiatric and behavioural items in order to create a new neuropsychiatric module that could be used as an addition to the Clinical Dementia Rating (CDR) plus National Alzheimer’s Coordinating Center Behaviour and Language Domains (NACC FTLD) rating scale. Results Overall, 46.4% of mutation carriers had neuropsychiatric symptoms (51.6% C9orf72 , 40.8% GRN , 46.6% MAPT ) compared with 24.5% of controls. Anxiety and depression were the most common in all genetic groups but fluctuated longitudinally and loaded separately in the PCA. Hallucinations and delusions loaded together, with the remaining neuropsychiatric symptoms loading with the core behavioural features of FTD. These results suggest using a single ‘psychosis’ neuropsychiatric module consisting of hallucinations and delusions. Adding this to the CDR plus NACC FTLD, called the CDR plus NACC FTLD-N, leads to a number of participants being scored more severely, including those who were previously considered asymptomatic now being scored as prodromal. Conclusions Neuropsychiatric symptoms occur in mutation carriers at all disease stages across all three genetic groups. However, only psychosis features provided additional staging benefit to the CDR plus NACC FTLD. Inclusion of these features brings us closer to optimising the rating scale for use in trials.
Although social cognitive dysfunction is a major feature of frontotemporal dementia (FTD), it has been poorly studied in familial forms. A key goal of studies is to detect early cognitive impairment using validated measures in large patient cohorts.We used the Revised Self-Monitoring Scale (RSMS) as a measure of socioemotional sensitivity in 730 participants from the genetic FTD initiative (GENFI) observational study: 269 mutation-negative healthy controls, 193 C9orf72 expansion carriers, 193 GRN mutation carriers and 75 MAPT mutation carriers. All participants underwent the standardised GENFI clinical assessment including the 'CDR® plus NACC FTLD' scale and RSMS. The RSMS total score and its two subscores, socioemotional expressiveness (EX score) and modification of self-presentation (SP score) were measured. Volumetric T1-weighted magnetic resonance imaging was available from 377 mutation carriers for voxel-based morphometry (VBM) analysis.The RSMS was decreased in symptomatic mutation carriers in all genetic groups but at a prodromal stage only in the C9orf72 (for the total score and both subscores) and GRN (for the modification of self-presentation subscore) groups. RSMS score correlated with disease severity in all groups. The VBM analysis implicated an overlapping network of regions including the orbitofrontal cortex, insula, temporal pole, medial temporal lobe and striatum.The RSMS indexes socioemotional impairment at an early stage of genetic FTD and may be a suitable outcome measure in forthcoming trials.
To compare registration strategies to align arterial spin labeling (ASL) with 3D T1-weighted (T1w) images, with the goal of reducing the between-subject variability of cerebral blood flow (CBF) images.Multi-center 3T ASL data were collected at eight sites with four different sequences in the multi-center GENetic Frontotemporal dementia Initiative (GENFI) study. In a total of 48 healthy controls, we compared the following image registration options: (I) which images to use for registration (perfusion-weighted images [PWI] to the segmented gray matter (GM) probability map (pGM) (CBF-pGM) or M0 to T1w (M0-T1w); (II) which transformation to use (rigid-body or non-rigid); and (III) whether to mask or not (no masking, M0-based FMRIB software library Brain Extraction Tool [BET] masking). In addition to visual comparison, we quantified image similarity using the Pearson correlation coefficient (CC), and used the Mann-Whitney U rank sum test.CBF-pGM outperformed M0-T1w (CC improvement 47.2% ± 22.0%; P < 0.001), and the non-rigid transformation outperformed rigid-body (20.6% ± 5.3%; P < 0.001). Masking only improved the M0-T1w rigid-body registration (14.5% ± 15.5%; P = 0.007).The choice of image registration strategy impacts ASL group analyses. The non-rigid transformation is promising but requires validation. CBF-pGM rigid-body registration without masking can be used as a default strategy. In patients with expansive perfusion deficits, M0-T1w may outperform CBF-pGM in sequences with high effective spatial resolution. BET-masking only improves M0-T1w registration when the M0 image has sufficient contrast.1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:131-140.
In this paper, we will consider the neuro-cognitive systems involved in mediating morality. Five main claims will be made. First, that there are multiple, partially separable neuro-cognitive architectures that mediate specific aspects of morality: social convention, care-based morality, disgust-based morality and fairness/justice. Second, that all aspects of morality, including social convention, involve affect. Third, that the neural system particularly important for social convention, given its role in mediating anger and responding to angry expressions, is ventrolateral prefrontal cortex. Fourth, that the neural systems particularly important for care-based morality are the amygdala and medial orbital frontal cortex. Fifth, that while Theory of Mind is not a prerequisite for the development of affect-based ‘automatic moral attitudes’, it is critically involved in many aspects of moral reasoning.
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