A data-driven model of brain volume changes in progressive supranuclear palsy

Supplementary material: Supplementary material is available at Brain Communications online.Copyright © The Author(s) 2022. The most common clinical phenotype of progressive supranuclear palsy is Richardson syndrome, characterized by levodopa unresponsive symmetric parkinsonism, with a vertical supranuclear gaze palsy, early falls and cognitive impairment. There is currently no detailed understanding of the full sequence of disease pathophysiology in progressive supranuclear palsy. Determining the sequence of brain atrophy in progressive supranuclear palsy could provide important insights into the mechanisms of disease progression, as well as guide patient stratification and monitoring for clinical trials. We used a probabilistic event-based model applied to cross-sectional structural MRI scans in a large international cohort, to determine the sequence of brain atrophy in clinically diagnosed progressive supranuclear palsy Richardson syndrome. A total of 341 people with Richardson syndrome (of whom 255 had 12-month follow-up imaging) and 260 controls were included in the study. We used a combination of 12-month follow-up MRI scans, and a validated clinical rating score (progressive supranuclear palsy rating scale) to demonstrate the longitudinal consistency and utility of the event-based model’s staging system. The event-based model estimated that the earliest atrophy occurs in the brainstem and subcortical regions followed by progression caudally into the superior cerebellar peduncle and deep cerebellar nuclei, and rostrally to the cortex. The sequence of cortical atrophy progresses in an anterior to posterior direction, beginning in the insula and then the frontal lobe before spreading to the temporal, parietal and finally the occipital lobe. This in vivo ordering accords with the post-mortem neuropathological staging of progressive supranuclear palsy and was robust under cross-validation. Using longitudinal information from 12-month follow-up scans, we demonstrate that subjects consistently move to later stages over this time interval, supporting the validity of the model. In addition, both clinical severity (progressive supranuclear palsy rating scale) and disease duration were significantly correlated with the predicted subject event-based model stage (P < 0.01). Our results provide new insights into the sequence of atrophy progression in progressive supranuclear palsy and offer potential utility to stratify people with this disease on entry into clinical trials based on disease stage, as well as track disease progression.We thank the research participants for their contribution to the study. The Dementia Research Centre is supported by Alzheimer’s Research UK, Alzheimer’s Society, Brain Research UK and The Wolfson Foundation. This work was supported by the National Institute of Health Research UCLH Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre Clinical Research Facility and the UK Dementia Research Institute (DRI), which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. The Progressive Supranuclear Palsy-Cortico-Basal Syndrome-Multiple System Atrophy (PROSPECT) study is funded by the PSP Association and CBD Solutions. The 4-repeat tauopathy neuroimaging initiative (4RTNI) and frontotemporal lobar degeneration neuroimaging initiative (FTLDNI) are funded by the National Institutes of Health Grant R01 AG038791 and through generous contributions from the Tau Research Consortium. Both are coordinated through the University of California, San Francisco, Memory and Aging Center. 4RTNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. W.J.S. is supported by a Wellcome Trust Clinical PhD fellowship (220582/Z/20/Z). M.B. is supported by a Fellowship award from the Alzheimer’s Society, UK (AS-JF-19a-004-517) and the UK Dementia Research Institute. N.P.O. is a UK Research and Innovation Future Leaders Fellow (MR/S03546X/1). D.C.A. is supported by the Engineering and Physical Sciences Research Council (EP/M020533/1); Medical Research Council (MR/T046422/1); Wellcome Trust (UNS113739). D.M.C. is supported by the UK Dementia Research Institute, as well as Alzheimer’s Research UK (ARUK-PG2017-1946) and the UCL/UCLH National Institute of Health Research Biomedical Research Centre. H.R.M. is supported by Parkinson’s UK, Cure Parkinson’s Trust, PSP Association, CBD Solutions, Drake Foundation, Medical Research Council, and the Michael J Fox Foundation. H.H. is supported by the National Institute of Health (R01AG038791, U19AG063911). L.V.V. is supported by National Institute of Health (R01AG038791). J.B.R. is supported by the Wellcome Trust (220258); National Institute of Health Research Cambridge Biomedical Research Centre (BRC-1215-20014); PSP Association; Evelyn Trust; Medical Research Council (SUAG051 R101400). A.B. is supported by National Institute of U19AG063911, R01AG038791, R01AG073482, U24AG057437, the Rainwater Charitable Foundation, the Bluefield Project to Cure FTD, the Alzheimer’s Association and the Association for Frontotemporal Degeneration. J.D.R. is supported by the Miriam Marks Brain Research UK Senior Fellowship and has received funding from a Medical Research Council Clinician Scientist Fellowship (MR/M008525/1) and the National Institute of Health Research Rare Disease Translational Research Collaboration (BRC149/NS/MH). P.A.W. is supported by a Medical Research Council Skills Development Fellowship (MR/T027770/1)

A unique androgen excess signature in idiopathic intracranial hypertension is linked to cerebrospinal fluid dynamics

Idiopathic intracranial hypertension (IIH) is a condition of unknown etiology, characterized by elevated intracranial pressure frequently manifesting with chronic headaches and visual loss. Similar to polycystic ovary syndrome (PCOS), IIH predominantly affects obese women of reproductive age. In this study, we comprehensively examined the systemic and cerebrospinal fluid (CSF) androgen metabolome in women with IIH in comparison with sex-, BMI-, and age-matched control groups with either simple obesity or PCOS (i.e., obesity and androgen excess). Women with IIH showed a pattern of androgen excess distinct to that observed in PCOS and simple obesity, with increased serum testosterone and increased CSF testosterone and androstenedione. Human choroid plexus expressed the androgen receptor, alongside the androgen-activating enzyme aldoketoreductase type 1C3. We show that in a rat choroid plexus cell line, testosterone significantly enhanced the activity of Na+/K+-ATPase, a surrogate of CSF secretion. We demonstrate that IIH patients have a unique signature of androgen excess and provide evidence that androgens can modulate CSF secretion via the choroid plexus. These findings implicate androgen excess as a potential causal driver and therapeutic target in IIH

Global Methylation Patterns in Idiopathic Pulmonary Fibrosis

BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF) is characterized by profound changes in the lung phenotype including excessive extracellular matrix deposition, myofibroblast foci, alveolar epithelial cell hyperplasia and extensive remodeling. The role of epigenetic changes in determining the lung phenotype in IPF is unknown. In this study we determine whether IPF lungs exhibit an altered global methylation profile.\ud \ud METHODOLOGY/PRINCIPAL FINDINGS: Immunoprecipitated methylated DNA from 12 IPF lungs, 10 lung adenocarcinomas and 10 normal histology lungs was hybridized to Agilent human CpG Islands Microarrays and data analysis was performed using BRB-Array Tools and DAVID Bioinformatics Resources software packages. Array results were validated using the EpiTYPER MassARRAY platform for 3 CpG islands. 625 CpG islands were differentially methylated between IPF and control lungs with an estimated False Discovery Rate less than 5%. The genes associated with the differentially methylated CpG islands are involved in regulation of apoptosis, morphogenesis and cellular biosynthetic processes. The expression of three genes (STK17B, STK3 and HIST1H2AH) with hypomethylated promoters was increased in IPF lungs. Comparison of IPF methylation patterns to lung cancer or control samples, revealed that IPF lungs display an intermediate methylation profile, partly similar to lung cancer and partly similar to control with 402 differentially methylated CpG islands overlapping between IPF and cancer. Despite their similarity to cancer, IPF lungs did not exhibit hypomethylation of long interspersed nuclear element 1 (LINE-1) retrotransposon while lung cancer samples did, suggesting that the global hypomethylation observed in cancer was not typical of IPF.\ud \ud CONCLUSIONS/SIGNIFICANCE: Our results provide evidence that epigenetic changes in IPF are widespread and potentially important. The partial similarity to cancer may signify similar pathogenetic mechanisms while the differences constitute IPF or cancer specific changes. Elucidating the role of these specific changes will potentially allow better understanding of the pathogenesis of IPF.\ud \u

Uncovering spatiotemporal patterns of atrophy in progressive supranuclear palsy using unsupervised machine learning

Data availability: Source data are not publicly available but non-commercial academic researcher requests may be made to the chief investigators of the seven source studies, subject to data access agreements and conditions that preserve participant anonymity. The underlying SuStaIn model code is publicly available at https://github.com/ucl-pond/pySuStaIn.68 .Supplementary data: available online at: https://academic.oup.com/braincomms/article/5/2/fcad048/7067775#398676040 .Copyright © The Author(s) 2023. To better understand the pathological and phenotypic heterogeneity of progressive supranuclear palsy and the links between the two, we applied a novel unsupervised machine learning algorithm (Subtype and Stage Inference) to the largest MRI data set to date of people with clinically diagnosed progressive supranuclear palsy (including progressive supranuclear palsy–Richardson and variant progressive supranuclear palsy syndromes). Our cohort is comprised of 426 progressive supranuclear palsy cases, of which 367 had at least one follow-up scan, and 290 controls. Of the progressive supranuclear palsy cases, 357 were clinically diagnosed with progressive supranuclear palsy–Richardson, 52 with a progressive supranuclear palsy–cortical variant (progressive supranuclear palsy–frontal, progressive supranuclear palsy–speech/language, or progressive supranuclear palsy–corticobasal), and 17 with a progressive supranuclear palsy–subcortical variant (progressive supranuclear palsy–parkinsonism or progressive supranuclear palsy–progressive gait freezing). Subtype and Stage Inference was applied to volumetric MRI features extracted from baseline structural (T1-weighted) MRI scans and then used to subtype and stage follow-up scans. The subtypes and stages at follow-up were used to validate the longitudinal consistency of subtype and stage assignments. We further compared the clinical phenotypes of each subtype to gain insight into the relationship between progressive supranuclear palsy pathology, atrophy patterns, and clinical presentation. The data supported two subtypes, each with a distinct progression of atrophy: a ‘subcortical’ subtype, in which early atrophy was most prominent in the brainstem, ventral diencephalon, superior cerebellar peduncles, and the dentate nucleus, and a ‘cortical’ subtype, in which there was early atrophy in the frontal lobes and the insula alongside brainstem atrophy. There was a strong association between clinical diagnosis and the Subtype and Stage Inference subtype with 82% of progressive supranuclear palsy–subcortical cases and 81% of progressive supranuclear palsy–Richardson cases assigned to the subcortical subtype and 82% of progressive supranuclear palsy–cortical cases assigned to the cortical subtype. The increasing stage was associated with worsening clinical scores, whilst the ‘subcortical’ subtype was associated with worse clinical severity scores compared to the ‘cortical subtype’ (progressive supranuclear palsy rating scale and Unified Parkinson’s Disease Rating Scale). Validation experiments showed that subtype assignment was longitudinally stable (95% of scans were assigned to the same subtype at follow-up) and individual staging was longitudinally consistent with 90% remaining at the same stage or progressing to a later stage at follow-up. In summary, we applied Subtype and Stage Inference to structural MRI data and empirically identified two distinct subtypes of spatiotemporal atrophy in progressive supranuclear palsy. These image-based subtypes were differentially enriched for progressive supranuclear palsy clinical syndromes and showed different clinical characteristics. Being able to accurately subtype and stage progressive supranuclear palsy patients at baseline has important implications for screening patients on entry to clinical trials, as well as tracking disease progression.W.J.S. is supported by a Wellcome Trust Clinical PhD fellowship (220582/Z/20/Z). C.S. is supported by the UK Research and Innovation Medical Research Council (MR/S03546X/1). M.B. is supported by a fellowship award from the Alzheimer’s Society, UK (AS-JF-19a-004-517), and the UK Dementia Research Institute. D.M.C. is supported by the UK Dementia Research Institute, as well as Alzheimer’s Research UK (ARUK-PG2017-1946), and the University College London/University College London Hospitals, National Institute for Health and Care Research Biomedical Research Centre. H.H. is supported by the National Institutes of Health (R01AG038791, U19AG063911). A.L.Y. is supported by a Skills Development Fellowship from the Medical Research Council (MR/T027800/1). N.P.O. is a UK Research and Innovation Future Leaders Fellow (MR/S03546X/1). L.V.V. is supported by the National Institutes of Health (R01AG038791, K23AG073514) and the Alzheimer’s Association. D.C.A. is supported by the Engineering and Physical Sciences Research Council (EP/M020533/1), Medical Research Council (MR/T046422/1), and Wellcome Trust (UNS113739). J.B.R. is supported by the Wellcome Trust (220258), National Institute for Health and Care Research Cambridge Biomedical Research Centre (BRC-1215-20014), PSP Association, Evelyn Trust, and Medical Research Council (SUAG051 R101400). H.R.M. is supported by Parkinson’s UK, Cure Parkinson’s Trust, PSP Association, CBD Solutions, Drake Foundation, Medical Research Council, and the Michael J Fox Foundation. A.L.B. is supported by the National Institutes of Health (U19AG063911, R01AG038791, R01AG073482, and U24AG057437), the Rainwater Charitable Foundation, the Bluefield Project to Cure FTD, and the Alzheimer’s Association and the Association for Frontotemporal Degeneration. J.D.R. is supported by the Miriam Marks Brain Research UK Senior Fellowship and has received funding from a Medical Research Council Clinician Scientist Fellowship (MR/M008525/1) and the National Institute for Health and Care Research Rare Disease Translational Research Collaboration (BRC149/NS/MH). P.A.W. is supported by a Medical Research Council Skills Development Fellowship (MR/T027770/1). The Dementia Research Centre is supported by Alzheimer’s Research UK, Alzheimer’s Society, Brain Research UK, and The Wolfson Foundation. This work was supported by the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre (LWENC) Clinical Research Facility, and the UK Dementia Research Institute, which receives its funding from UK DRI Ltd., funded by the UK Medical Research Council, Alzheimer’s Society, and Alzheimer’s Research UK. The PROSPECT study is funded by the PSP Association and CBD Solutions. The 4-Repeat Tauopathy Neuroimaging Initiative (4RTNI) and FTLDNI are funded by the National Institutes of Health Grant (R01 AG038791) and through generous contributions from the Tau Research Consortium. Both are coordinated through the University of California, San Francisco, Memory and Aging Center. 4RTNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California

Mesenchymal cell survival in airway and interstitial pulmonary fibrosis

Fibrotic reactions in the airways of the lung or the pulmonary interstitium are a common pathologic outcome after exposure to a wide variety of toxic agents, including metals, particles or fibers. The survival of mesenchymal cells (fibroblasts and myofibroblasts) is a key factor in determining whether a fibroproliferative response that occurs after toxic injury to the lung will ultimately resolve or progress to a pathologic state. Several polypeptide growth factors, including members of the platelet-derived growth factor (PDGF) family and the epidermal growth factor (EGF) family, are prosurvival factors that stimulate a replicative and migratory mesenchymal cell phenotype during the early stages of lung fibrogenesis. This replicative phenotype can progress to a matrix synthetic phenotype in the presence of transforming growth factor-β1 (TGF-β1). The resolution of a fibrotic response requires growth arrest and apoptosis of mesenchymal cells, whereas progressive chronic fibrosis has been associated with mesenchymal cell resistance to apoptosis. Mesenchymal cell survival or apoptosis is further influenced by cytokines secreted during Th1 inflammation (e.g., IFN-γ) or Th2 inflammation (e.g., IL-13) that modulate the expression of growth factor activity through the STAT family of transcription factors. Understanding the mechanisms that regulate the survival or death of mesenchymal cells is central to ultimately developing therapeutic strategies for lung fibrosis

Heterogeneity of Microglial Activation in the Innate Immune Response in the Brain

The immune response in the brain has been widely investigated and while many studies have focused on the proinflammatory cytotoxic response, the brain’s innate immune system demonstrates significant heterogeneity. Microglia, like other tissue macrophages, participate in repair and resolution processes after infection or injury to restore normal tissue homeostasis. This review examines the mechanisms that lead to reduction of self-toxicity and to repair and restructuring of the damaged extracellular matrix in the brain. Part of the resolution process involves switching macrophage functional activation to include reduction of proinflammatory mediators, increased production and release of anti-inflammatory cytokines, and production of cytoactive factors involved in repair and reconstruction of the damaged brain. Two partially overlapping and complimentary functional macrophage states have been identified and are called alternative activation and acquired deactivation. The immunosuppressive and repair processes of each of these states and how alternative activation and acquired deactivation participate in chronic neuroinflammation in the brain are discussed