Dataset Information

Global alterations to the choroid plexus blood-CSF barrier in amyotrophic lateral sclerosis.

ABSTRACT: The choroid plexus (CP) is a highly vascularized structure located in the ventricles that forms the blood-CSF barrier (BCSFB) and separates the blood from the cerebrospinal fluid (CSF). In addition to its role as a physical barrier, the CP functions in CSF secretion, transport of nutrients into the central nervous system (CNS) and a gated point of entry of circulating immune cells into the CNS. Aging and neurodegeneration have been reported to affect CP morphology and function and increase protein leakage from blood to the CSF. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease associated with both upper and lower motor neuron loss, as well as altered proteomic and metabolomic signatures in the CSF. The role of the BCSFB and the CP in ALS is unknown. Here we describe a transcriptomic and ultrastructural analysis of BCSFB and CP alterations in human postmortem tissues from ALS and non-neurologic disease controls. ALS-CP exhibited widespread disruptions in tight junctional components of the CP epithelial layer and vascular integrity. In addition, we detected loss of pericytes around ALS blood vessels, accompanied by activation of platelet aggregation markers vWF and Fibrinogen, reminiscent of vascular injury. To investigate the immune component of ALS-CP, we conducted a comprehensive analysis of cytokines and chemokine panels in CP lysates and found a significant down-regulation of M-CSF and V-CAM1 in ALS, as well as up-regulation of VEGF-A protein. This phenotype was accompanied by an infiltration of MERTK positive macrophages into the parenchyma of the ALS-CP when compared to controls. Taken together, we demonstrate widespread structural and functional disruptions of the BCSFB in human ALS increasing our understanding of the disease pathology and identifying potential new targets for ALS therapeutic development.

SUBMITTER: Saul J

PROVIDER: S-EPMC7318439 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Global alterations to the choroid plexus blood-CSF barrier in amyotrophic lateral sclerosis.

Saul J J Hutchins E E Reiman R R Saul M M Ostrow L W LW Harris B T BT Van Keuren-Jensen K K Bowser R R Bakkar N N

Acta neuropathologica communications 20200626 1

The choroid plexus (CP) is a highly vascularized structure located in the ventricles that forms the blood-CSF barrier (BCSFB) and separates the blood from the cerebrospinal fluid (CSF). In addition to its role as a physical barrier, the CP functions in CSF secretion, transport of nutrients into the central nervous system (CNS) and a gated point of entry of circulating immune cells into the CNS. Aging and neurodegeneration have been reported to affect CP morphology and function and increase prote ...[more]

PMID: 32586411

Similar Datasets

Project description:Amyotrophic lateral sclerosis (ALS) is an incurable and rapidly progressive neurological disorder. Biomarkers are critical to understanding disease causation, monitoring disease progression and assessing the efficacy of treatments. However, robust peripheral biomarkers are yet to be identified. Neuroinflammation and breakdown of the blood-brain barrier (BBB) are common to familial and sporadic ALS and may produce a unique biomarker signature in peripheral blood. Using cytometric bead array (n = 15 participants per group (ALS or control)) and proteome profiling (n = 6 participants per group (ALS or control)), we assessed a total of 106 serum cytokines, growth factors, and BBB breakdown markers in the serum of control and ALS participants. Further, primary human brain pericytes, which maintain the BBB, were used as a biosensor of inflammation following pre-treatment with ALS serum. Principal components analysis of all proteome profile data showed no clustering of control or ALS sera, and no individual serum proteins met the threshold for statistical difference between ALS and controls (adjusted P values). However, the 20 most changed proteins between control and ALS sera showed a medium effect size (Cohen's d = 0.67) and cluster analysis of their levels together identified three sample subsets; control-only, mixed control-ALS, and ALS-only. These 20 proteins were predominantly pro-angiogenic and growth factors, including fractalkine, BDNF, EGF, PDGF, Dkk-1, MIF and angiopoietin-2. S100β, a protein highly concentrated in glial cells and therefore a marker of BBB leakage when found in blood, was unchanged in ALS serum, suggesting that serum protein profiles were reflective of peripheral rather than CNS biofluids. Finally, primary human brain pericytes remained proliferative and their secretome was unchanged by chronic exposure to ALS serum. Our exploratory study suggests that individual serum cytokine levels may not be robust biomarkers in small studies of ALS, but that larger studies using multiplexed analysis of pro-angiogenic and growth factors may identify a peripheral signature of ALS pathogenesis.

Project description:Primary lateral sclerosis is a sporadic disorder characterized by slowly progressive corticospinal dysfunction. Primary lateral sclerosis differs from amyotrophic lateral sclerosis by its lack of lower motor neuron signs and long survival. Few pathological studies have been carried out on patients with primary lateral sclerosis, and the relationship between primary lateral sclerosis and amyotrophic lateral sclerosis remains uncertain. To detect in vivo structural differences between the two disorders, diffusion tensor imaging of white matter tracts was carried out in 19 patients with primary lateral sclerosis, 18 patients with amyotrophic lateral sclerosis and 19 age-matched controls. Fibre tracking was used to reconstruct the intracranial portion of the corticospinal tract and three regions of the corpus callosum: the genu, splenium and callosal fibres connecting the motor cortices. Both patient groups had reduced fractional anisotropy, a measure associated with axonal organization, and increased mean diffusivity of the reconstructed corticospinal and callosal motor fibres compared with controls, without changes in the genu or splenium. Voxelwise comparison of the whole brain white matter using tract-based spatial statistics confirmed the differences between patients and controls in the diffusion properties of the corticospinal tracts and motor fibres of the callosum. This analysis further revealed differences in the regional distribution of white matter alterations between the patient groups. In patients with amyotrophic lateral sclerosis, the greatest reduction in fractional anisotropy occurred in the distal portions of the intracranial corticospinal tract, consistent with a distal axonal degeneration. In patients with primary lateral sclerosis, the greatest loss of fractional anisotropy and mean diffusivity occurred in the subcortical white matter underlying the motor cortex, with reduced volume, suggesting tissue loss. Clinical measures of upper motor neuron dysfunction correlated with reductions in fractional anisotropy in the corticospinal tract in patients with amyotrophic lateral sclerosis and increased mean diffusivity and volume loss of the corticospinal tract in patients with primary lateral sclerosis. Changes in the diffusion properties of the motor fibres of the corpus callosum were strongly correlated with changes in corticospinal fibres in patients, but not in controls. These findings indicate that degeneration is not selective for corticospinal neurons, but affects callosal neurons within the motor cortex in motor neuron disorders.

Project description:BACKGROUND:Amyotrophic lateral sclerosis (ALS) is a highly progressive and debilitating neurodegenerative disease, which usually leads to the death of affected individuals within a few years after the onset of symptoms. ALS is currently incurable and very little is known about its pathophysiology. Finding validated biomarkers will help us to advance our understanding of ALS etiology and find better strategies for early diagnosis and management of the disease. The main aim of the present systematic review is to evaluate the concentration of 11 frequently reported biomarkers for ALS in peripheral blood and CSF of patients diagnosed with ALS compared with controls. METHODS:This systematic review protocol has been established according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocol (PRISMA-P) 2015 guideline. We will include all types of observational studies with human subjects that investigated the concentrations of intended biomarkers (amyloid beta (Aβ-42), tau and phosphorylated tau (p-Tau), neurofilaments, S100β, cystatin C, progranulin (PGRN), glial fibrillary acidic protein (GFAP), monocyte chemoattractant protein-1 (MCP-1), brain-derived neurotrophic factor (BDNF), TAR DNA-binding protein-43 (TDP43), YKL-40, and CHIT1 in CSF or peripheral blood of ALS patients for initial assessment. Also, we will include case series with a minimum of 10 cases and clinical trials which have measured baseline biomarker levels. Case studies, case reports, reviews, letters, and animal and in vitro studies will be excluded. Multiple electronic databases including Cochrane Library, MEDLINE (PubMed), ISI Web of Science, and EMBASE will be searched to find all eligible articles published since 1980. No language restriction will be applied. All titles and abstracts retrieved by searching information sources will be evaluated independently by two authors against the eligibility criteria. The following information will be extracted from each included study by two independent authors: bibliographic details (first author, study title, year of publication, country), demographics and clinical information (number of patients and controls, type of ALS and controls, study design, age, gender, specimen, biomarkers levels, ALS functional rating scale Revised (ALSFRS-R), duration of disease), and measurements (method, value type, biomarkers levels). We will use the extracted mean and standard deviation (SD) of biomarkers concentrations to calculate the standardized mean difference (SMD) and 95% confidence intervals (CI). The primary outcome measures are the mean difference of biomarker levels between ALS patients and controls, different types of ALS, and ALS patients with genetic mutations. DISCUSSION:We will systematically review the literature and analyze studies of biomarker level in CSF and peripheral blood of patients with ALS and controls. The results will help us to identify biomarkers with possible diagnostic and prognostic value. SYSTEMATIC REVIEW REGISTRATION:PROSPERO CRD42017078127.

Dataset Information

Global alterations to the choroid plexus blood-CSF barrier in amyotrophic lateral sclerosis.

Publications

Global alterations to the choroid plexus blood-CSF barrier in amyotrophic lateral sclerosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets