Blood–Brain Barrier Disruption Is Not Associated With Disease Aggressiveness in Amyotrophic Lateral Sclerosis

Prell, Tino; Vlad, Benjamin; Gaur, Nayana; Stubendorff, Beatrice; Großkreutz, Julian

doi:10.3389/fnins.2021.656456

Cited by 14 publications

(11 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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.

View full text Add to dashboard Cite

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.

show abstract

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.

View full text Add to dashboard Cite

show abstract

“…Therefore, patients with the bulbar phenotype worsen rapidly, but they do not manifest the same effects on the BBB and BSCB dysfunction parameters measured in our study and altered in the spinal onset ALS cohort showing the elevation of CSF proteins and QAlb. These results are reinforced by Prell et al, who also found an association with increased levels of albumin in CSF, spinal-onset disease and BBB damage [ 39 ].…”

Section: Discussionmentioning

confidence: 69%

Elevated Cerebrospinal Fluid Proteins and Albumin Determine a Poor Prognosis for Spinal Amyotrophic Lateral Sclerosis

Assialioui

Domínguez

Ferrer

et al. 2022

IJMS

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is a heterogeneous disease, both in its onset phenotype and in its rate of progression. The aim of this study was to establish whether the dysfunction of the blood–brain barrier (BBB) and blood–spinal cord barrier (BSCB) measured through cerebrospinal fluid (CSF) proteins and the albumin-quotient (QAlb) are related to the speed of disease progression. An amount of 246 patients diagnosed with ALS were included. CSF and serum samples were determined biochemically for different parameters. Survival analysis based on phenotype shows higher probability of death for bulbar phenotype compared to spinal phenotype (p-value: 0.0006). For the effect of CSF proteins, data shows an increased risk of death for spinal ALS patients as the value of CSF proteins increases. The same model replicated for CSF albumin yielded similar results. Statistical models determined that the lowest cut-off value for CSF proteins able to differentiate patients with a good prognosis and worse prognosis corresponds to CSF proteins ≥ 0.5 g/L (p-value: 0.0189). For the CSF albumin, the QAlb ≥0.65 is associated with elevated probability of death (p-value: 0.0073). High levels of QAlb are a bad prognostic indicator for the spinal phenotype, in addition to high CSF proteins levels that also act as a marker of poor prognosis.

show abstract

“…The gadolinium leakage normalized within 24 h, showing the reversibility of the procedure but also the absence of signs of previous BBB disruption in these patients. Moreover, elevation of QAlb has been reported in only 20–50% of ALS patients, suggesting that BBB disruption would not appear in all individuals [ 34 , 35 , 36 ]. Recently, Waters et al showed that BSCB disruption, evidenced by hemoglobin leakage in postmortem human tissues, would be predominant in the thoracic spinal cord while motoneurons loss and TDP-43 deposits were mainly observed in the cervical and lumbar spinal cord.…”

Section: Bbb Alterations In Als and Their Consequencesmentioning

confidence: 99%

“…Moreover, CSF total protein, CSF IgG, and QIgG were significant indicators of disease progression. On the other side, Prell et al evaluated the QAlb in a cohort of 160 ALS patients and 31 ALS mimicking conditions but did not find any significant association with the disease evolution [ 34 ].…”

Section: Bbb Alterations In Als and Their Consequencesmentioning

confidence: 99%

Taking Advantages of Blood–Brain or Spinal Cord Barrier Alterations or Restoring Them to Optimize Therapy in ALS?

Alarcan

Ojaimi

Lanznaster

et al. 2022

JPM

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder that still lacks an efficient therapy. The barriers between the central nervous system (CNS) and the blood represent a major limiting factor to the development of drugs for CNS diseases, including ALS. Alterations of the blood–brain barrier (BBB) or blood–spinal cord barrier (BSCB) have been reported in this disease but still require further investigations. Interestingly, these alterations might be involved in the complex etiology and pathogenesis of ALS. Moreover, they can have potential consequences on the diffusion of candidate drugs across the brain. The development of techniques to bypass these barriers is continuously evolving and might open the door for personalized medical approaches. Therefore, identifying robust and non-invasive markers of BBB and BSCB alterations can help distinguish different subgroups of patients, such as those in whom barrier disruption can negatively affect the delivery of drugs to their CNS targets. The restoration of CNS barriers using innovative therapies could consequently present the advantage of both alleviating the disease progression and optimizing the safety and efficiency of ALS-specific therapies.

show abstract

Blood–Brain Barrier Disruption Is Not Associated With Disease Aggressiveness in Amyotrophic Lateral Sclerosis

Cited by 14 publications

References 20 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

Elevated Cerebrospinal Fluid Proteins and Albumin Determine a Poor Prognosis for Spinal Amyotrophic Lateral Sclerosis

Taking Advantages of Blood–Brain or Spinal Cord Barrier Alterations or Restoring Them to Optimize Therapy in ALS?

Contact Info

Product

Resources

About