Cerebrospinal fluid cytotoxicity does not affect survival in amyotrophic lateral sclerosis

Galán, Lucía; Matías‐Guiu, Jorge; Yáñez, Matilde; Pytel, Vanesa; Guerrero-Solá, A.; Vela-Souto, A.; Arranz-Tagarro, Juan-Alberto; Gómez‐Pinedo, Ulises; Garcı́a, Antonio G.

doi:10.1111/ane.12717

Cited by 7 publications

(8 citation statements)

References 30 publications

(56 reference statements)

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“…Two studies also assessed cytotoxicity within ALS patient populations. In the first study, which evaluated CSF cytotoxicity in 31 patients with ‘probable’ or ‘definite’ ALS at the time of diagnosis, 67.7% of patients were considered to possess cytotoxic CSF, with cytotoxicity being defined as a reduction in cell survival greater or equal to 25% compared to control ( Galán et al , 2017 ). The second study compared CSF cytotoxicity between sporadic ALS patients with a high concentration of 4‐hydroxynonenal with those with a low concentration of 4‐hydroxynonenal, and reported a significant difference at both 1% and 10% CSF concentration ( Smith et al , 1998 ).…”

Section: Resultsmentioning

confidence: 99%

Cerebrospinal fluid cytotoxicity in amyotrophic lateral sclerosis: a systematic review of in vitro studies

Kwong

Gregory

Pal

et al. 2020

Brain Communications

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Various studies have suggested that a neurotoxic cerebrospinal fluid (CSF) profile could be implicated in amyotrophic lateral sclerosis (ALS). Here, we systematically review the evidence for CSF cytotoxicity in ALS and explore its clinical correlates. We searched the following databases with no restrictions on publication date: PubMed, Embase and Web of Science. All studies that investigated cytotoxicity in vitro following exposure to CSF from ALS patients were considered for inclusion. Meta-analysis could not be performed, and findings were instead narratively summarised. 28 studies were included in our analysis. Both participant characteristics and study conditions including CSF concentration, exposure time and culture model varied considerably across studies. Of 22 studies assessing cell viability relative to controls, 19 studies reported a significant decrease following exposure to ALS-CSF, while three early studies failed to observe any difference. Seven of eight studies evaluating apoptosis observed significant increases in the levels of apoptotic markers following exposure to ALS-CSF, with the remaining study reporting a qualitative difference. Although five studies investigated the possible relationship between CSF cytotoxicity and patient characteristics, such as age, gender and disease duration, none demonstrated an association with any of the factors. In conclusion, our analysis suggests that CSF cytotoxicity is a feature of sporadic and possibly also of familial forms of ALS. Further research is, however, required to better characterise its underlying mechanisms and to establish its possible contribution to ALS pathophysiology.

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Section: Resultsmentioning

confidence: 99%

Cerebrospinal fluid cytotoxicity in amyotrophic lateral sclerosis: a systematic review of in vitro studies

Kwong

Gregory

Pal

et al. 2020

Brain Communications

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“…We could not observe a significant reduction of MNs or neurons in general by exposition to ALS-CSF compared to control-CSF, when healthy donor-derived MNs were treated. Several reasons could explain this difference from results from murine primary cortical/spinal motor neuron cultures [3,47], including human vs. murine cell culture system, medium composition or preanalytic CSF preparation. Another major concern regards the cellular age.…”

Section: Discussionmentioning

confidence: 99%

“…However, this was necessary due to the long time culture conditions and the protocol for human iPSC-derived MNs with the need for medium change every other day (Figure 1). Thus, we cannot answer the question as to whether single ALS patient-derived CSF might vary depending on clinical parameters such as ALS subtype, disease stage or even family background [47]. However, the study rationale was to investigate whether CSF from sporadic ALS patients could induce an MN-like degeneration in the dish, and thus we intended to analyze group differences rather than ALS subtype or individual patient's specific differences.…”

Section: Discussionmentioning

confidence: 99%

Human Spinal Motor Neurons Are Particularly Vulnerable to Cerebrospinal Fluid of Amyotrophic Lateral Sclerosis Patients

Bräuer

Günther

Sterneckert

et al. 2020

IJMS

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Amyotrophic lateral sclerosis (ALS) is the most common and devastating motor neuron (MN) disease. Its pathophysiological cascade is still enigmatic. More than 90% of ALS patients suffer from sporadic ALS, which makes it specifically demanding to generate appropriate model systems. One interesting aspect considering the seeding, spreading and further disease development of ALS is the cerebrospinal fluid (CSF). We therefore asked whether CSF from sporadic ALS patients is capable of causing disease typical changes in human patient-derived spinal MN cultures and thus could represent a novel model system for sporadic ALS. By using induced pluripotent stem cell (iPSC)-derived MNs from healthy controls and monogenetic forms of ALS we could demonstrate a harmful effect of ALS-CSF on healthy donor-derived human MNs. Golgi fragmentation—a typical finding in lower organism models and human postmortem tissue—was induced solely by addition of ALS-CSF, but not control-CSF. No other neurodegenerative hallmarks—including pathological protein aggregation—were found, underpinning Golgi fragmentation as early event in the neurodegenerative cascade. Of note, these changes occurred predominantly in MNs, the cell type primarily affected in ALS. We thus present a novel way to model early features of sporadic ALS.

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“…We have read the article written by Galán et al, 1 First, the association between independent variables with survival rate was assessed using the Cox PH models, while PH assumption as one of the major assumptions has not been evaluated graphically or using the appropriate methods such as time-dependent covariates methods. This assumption has been violated in the study conducted by Galán and colleagues which is shown in their article as Figure 1.…”

Section: Cerebrospinal Fluid Cytotoxicity Does Not Affect Survival Inmentioning

confidence: 99%