Blood-spinal cord barrier leakage is independent of motor neuron pathology in ALS

Waters, Sarah L.; Dieriks, Birger; Swanson, Molly E. V.; Zhang, Yibin; Grimsey, Natasha L.; Murray, Helen C.; Turner, Clinton; Waldvogel, Henry J.; Faull, Richard L.M.; An, Jiyan; Bowser, Robert; Curtis, Maurice A.; Dragunow, Mike; Scotter, Emma L.

doi:10.1101/704270

Cited by 7 publications

(11 citation statements)

References 45 publications

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“…It relies on the assumption of therapeutic extravasation from the vascular compartment to the CNS parenchyma and then to the subarachnoid space without direct CSF excretion at the choroid plexus (i.e., via the BCSFB) or complete therapeutic metabolism within neural tissue. Pharmacokinetic studies investigating CSF/serum concentration ratios of multiple ALS therapeutics have typically demonstrated low CSF/serum ratios suggesting limited therapeutic access across the BCNSB (Sussmuth et al, 2010 ; Wu et al, 2020 ; Prell et al, 2021 ; Waters et al, 2021 ).…”

Section: Resultsmentioning

confidence: 99%

Breached Barriers: A Scoping Review of Blood-Central Nervous System Barrier Pathology in Amyotrophic Lateral Sclerosis

Mirian

Moszczynski

Soleimani

et al. 2022

Front. Cell. Neurosci.

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IntroductionRecent studies have implicated changes in the blood-central nervous system barriers (BCNSB) in amyotrophic lateral sclerosis (ALS). The objective of this scoping review is to synthesize the current evidence for BCNSB structure and functional abnormalities in ALS studies and propose how BCNSB pathology may impact therapeutic development.MethodsA literature search was conducted using Ovid Medline, EMBASE, and Web of Science, from inception to November 2021 and limited to entries in English language. Simplified search strategy included the terms ALS/motor neuron disease and [BCNSB or blood-brain barrier (BBB) or blood-spinal cord barrier (BSCB)]. Henceforth, BCNSB is used as a term that is inclusive of the BBB and BSCB. Four independent reviewers conducted a title and abstract screening, hand-searched the reference lists of review papers, and performed a full text review of eligible studies. Included studies were original peer-reviewed full text publications, evaluating the structure and function of the BCNSB in preclinical models of ALS, clinical ALS, or postmortem human ALS tissue. There was no restriction on study design. The four reviewers independently extracted the data.ResultsThe search retrieved 2,221 non-duplicated articles and 48 original studies were included in the synthesis. There was evidence that the integrity of the BCNSB is disrupted throughout the course of the disease in rodent models, beginning prior to symptom onset and detectable neurodegeneration. Increased permeability, pharmacoresistance with upregulated efflux transporters, and morphological changes in the supporting cells of the BCNSB, including pericytes, astrocytes, and endothelial cells were observed in animal models. BCNSB abnormalities were also demonstrated in postmortem studies of ALS patients. Therapeutic interventions targeting BCNSB dysfunction were associated with improved motor neuron survival in animal models of ALS.ConclusionBCNSB structural and functional abnormalities are likely implicated in ALS pathophysiology and may occur upstream to neurodegeneration. Promising therapeutic strategies targeting BCNSB dysfunction have been tested in animals and can be translated into ALS clinical trials.

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Section: Resultsmentioning

confidence: 99%

Breached Barriers: A Scoping Review of Blood-Central Nervous System Barrier Pathology in Amyotrophic Lateral Sclerosis

Mirian

Moszczynski

Soleimani

et al. 2022

Front. Cell. Neurosci.

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“…Similarly, blood-CNS barrier (BCNSB) disruption has also been reported in ALS. For example, blood-spinal cord barrier (BSCB) breakdown was detected in rodent models of ALS prior to motor neuron degeneration and neuroinflammation and worsens with disease progression [ 40 – 45 ], although one human study reported that BSCB leakage was independent of motor neuron pathology in ALS [ 46 ]. Postmortem studies revealed structural and functional impairment of the BSCB in gray and white matter microvessels of medulla and spinal cord tissue from ALS patients [ 45 , 47 , 48 ].…”

Section: Introductionmentioning

confidence: 99%

Basal lamina changes in neurodegenerative disorders

Nguyen

Bix

Yao

2021

Mol Neurodegeneration

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Background Neurodegenerative disorders are a group of age-associated diseases characterized by progressive degeneration of the structure and function of the CNS. Two key pathological features of these disorders are blood-brain barrier (BBB) breakdown and protein aggregation. Main body The BBB is composed of various cell types and a non-cellular component---the basal lamina (BL). Although how different cells affect the BBB is well studied, the roles of the BL in BBB maintenance and function remain largely unknown. In addition, located in the perivascular space, the BL is also speculated to regulate protein clearance via the meningeal lymphatic/glymphatic system. Recent studies from our laboratory and others have shown that the BL actively regulates BBB integrity and meningeal lymphatic/glymphatic function in both physiological and pathological conditions, suggesting that it may play an important role in the pathogenesis and/or progression of neurodegenerative disorders. In this review, we focus on changes of the BL and its major components during aging and in neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). First, we introduce the vascular and lymphatic systems in the CNS. Next, we discuss the BL and its major components under homeostatic conditions, and summarize their changes during aging and in AD, PD, and ALS in both rodents and humans. The functional significance of these alterations and potential therapeutic targets are also reviewed. Finally, key challenges in the field and future directions are discussed. Conclusions Understanding BL changes and the functional significance of these changes in neurodegenerative disorders will fill the gap of knowledge in the field. Our goal is to provide a clear and concise review of the complex relationship between the BL and neurodegenerative disorders to stimulate new hypotheses and further research in this field.

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“…In addition to IgG, Winker et al noted haemoglobin, fibrinogen and thrombin in the ALS cervical spinal cord (8 sporadic ALS cases, 3 familial ALS cases) but not in non-ALS controls (5 cases) (Winkler, Sengillo, Sullivan, Henkel, Appel & Zlokovic, 2013). In line with these postmortem findings, increased IgG (1.26-fold) and albumin (1.28-fold) has been reported by Leonardi et al (Leonardi, Abbruzzese, Arata, Cocito & Vische, 1984) (Waters et al, 2021) . Consistently, these studies demonstrate that CNS barrier permeability is generally increased in individuals with ALS, which is very likely a result of the ultrastructural abnormality and reduced expression of TJs at the ALS CNS barriers.…”

Section: Leaky Cns Barriersmentioning

confidence: 85%

“…In postmortem ALS human spinal cord, electron microscopy and immunohistochemistry revealed swelling and cytoplasmic vacuolisation of microvascular endothelial cells, degeneration of pericytes and detachment of astrocyte end-feet processes from endothelial cells (Garbuzova- Davis et al, 2012;Miyazaki et al, 2011;Sasaki, 2015;Yamadera et al, 2015). Studies also reported increased (Garbuzova- Davis et al, 2012;Waters et al, 2021) or decreased (Miyazaki et al, 2011;Ono et al, 1998) collagen content in the basement membrane of the spinal cord microvasculature in ALS patients. Reduced collagen content in the basement membrane can be to due cellular damage, whereas a thickened basement membrane could be a result of repetitive regeneration.…”

Section: Ultrastructural Modificationsmentioning

confidence: 98%

Altered Blood-Brain Barrier and Blood-Spinal Cord Barrier Dynamics in Amyotrophic Lateral Sclerosis: Impact on Medication Efficacy and Safety

Pan

Nicolazzo

2021

Preprint

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The access of drugs into the central nervous system (CNS) is regulated by the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB). A large body of evidence supports perturbation of these barriers in neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. Modifications to the BBB and BSCB are also reported in amyotrophic lateral sclerosis (ALS), albeit these modifications have received less attention relative to those in other neurodegenerative diseases. Such alterations to the BBB and BSCB have the potential to impact on CNS exposure of drugs in ALS, modulating the effectiveness of drugs intended to reach the brain and the toxicity of drugs that are not intended to reach the brain. Given the clinical importance of these phenomena, this review will summarise reported modifications to the BBB and BSCB in ALS, discuss their impact on CNS drug exposure and suggest further research directions so as to optimise medicine use in people with ALS.

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Blood-spinal cord barrier leakage is independent of motor neuron pathology in ALS

Cited by 7 publications

References 45 publications

Breached Barriers: A Scoping Review of Blood-Central Nervous System Barrier Pathology in Amyotrophic Lateral Sclerosis

Breached Barriers: A Scoping Review of Blood-Central Nervous System Barrier Pathology in Amyotrophic Lateral Sclerosis

Basal lamina changes in neurodegenerative disorders

Altered Blood-Brain Barrier and Blood-Spinal Cord Barrier Dynamics in Amyotrophic Lateral Sclerosis: Impact on Medication Efficacy and Safety

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