Population-Based Evaluation of Total Protein in Cerebrospinal Fluid

Fautsch, Kalli J.; Block, Darci R.; Graff‐Radford, Jonathan; Wang, Rui; Craver, Emily C.; Hodge, David O.; Cutsforth‐Gregory, Jeremy K.; Kilgore, Khin P.; Petersen, Ronald C.; Knopman, David S.; Flanagan, Eoin P.; Toledano, Michel; Mielke, Michelle M.; Bhatti, M. Tariq; Chen, John J.

doi:10.1016/j.mayocp.2022.10.012

Cited by 10 publications

(7 citation statements)

References 23 publications

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“…31 A recent study evaluating total CSF protein levels in a community-based population of 633 participants (mean age 70.9 ± 11.6 years), documented mean CSF protein 52.2 ± 18.4 mg/dl, with 95% confidence interval of 24.0–93.4 mg/dl (range, 14.0–148.0 mg/dl). 33 Age, male sex and diabetes were independently associated with higher CSF protein levels. Moreover, CSF analysis was repeated in 66 individuals within 2.5 years and the coefficient of repeatability was 26.1 mg/dl, with 11 cases showing a difference of >20 mg/dl between serial measurements.…”

Section: Resultsmentioning

confidence: 94%

European Stroke Organisation (ESO) guidelines on Primary Angiitis of the Central Nervous System (PACNS)

Pascarella,

Antonenko,

Boulouis

et al. 2023

European Stroke Journal

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The European Stroke Organisation (ESO) guideline on Primary Angiitis of the Central Nervous System (PACNS), developed according to ESO standard operating procedures (SOP) and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology, was elaborated to assist clinicians in the diagnostic and treatment pathway of patients with PACNS in their decision making. A working group involving vascular neurologists, neuroradiologists, rheumatologists, a neuropathologist and a methodologist identified 17 relevant clinical questions; these were addressed according to the patient/population, intervention, comparison and outcomes (PICO) framework and systematic literature reviews were performed. Notably, each PICO was addressed with respect to large vessel (LV)-PACNS and small vessel (SV)-PACNS. Data to answer many questions were scarce or lacking and the quality of evidence was very low overall, so, for some PICOs, the recommendations reflect the ongoing uncertainty. When the absence of sufficient evidence precluded recommendations, Expert Consensus Statements were formulated. In some cases, this applied to interventions in the diagnosis and treatment of PACNS which are embedded widely in clinical practice, for example patterns of cerebrospinal fluid (CSF) and Magnetic Resonance Imaging (MRI) abnormalities. CSF analysis for hyperproteinorrachia and pleocytosis does not have evidence supporting their use as diagnostic tools. The working group recommended that caution is employed in the interpretation of non-invasive vascular imaging due to lack of validation and the different sensitivities in comparison with digital subtraction angiography (DSA) and histopathological analyses. Moreover, there is not a neuroimaging pattern specific for PACNS and neurovascular issues are largely underreported in PACNS patients. The group’s recommendations on induction and maintenance of treatment and for primary or secondary prevention of vascular events also reflect uncertainty due to lack of evidence. Being uncertain the role and practical usefulness of current diagnostic criteria and being not comparable the main treatment strategies, it is suggested to have a multidisciplinary team approach in an expert center during both work up and management of patients with suspected PACNS. Highlighting the limitations of the currently accepted diagnostic criteria, we hope to facilitate the design of multicenter, prospective clinical studies and trials. A standardization of neuroimaging techniques and reporting to improve the level of evidence underpinning interventions employed in the diagnosis and management of PACNS. We anticipate that this guideline, the first comprehensive European guideline on PACNS management using GRADE methodology, will assist clinicians to choose the most effective management strategy for PACNS.

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Section: Resultsmentioning

confidence: 94%

European Stroke Organisation (ESO) guidelines on Primary Angiitis of the Central Nervous System (PACNS)

Pascarella,

Antonenko,

Boulouis

et al. 2023

European Stroke Journal

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“…The CSF SOD1 activity levels increased with age (Figure S2b) in agreement with our previous studies (Jacobsson et al, 2001;Zetterstrom et al, 2011). The total protein levels likewise vary much and increase with age (Figure S2f) (Fautsch et al, 2023). The reason for (which was not certified by peer review) is the author/funder.…”

Section: Sod1 Activity In Csf Of Als Patients and Controlsmentioning

confidence: 99%

“…The copyright holder for this preprint this version posted June 16, 2024. ; https://doi.org/10.1101/2024.06.15.599161 doi: bioRxiv preprint the increase of total protein is not completely understood but may involve an age-dependent reduction in CSF turnover rates (Fautsch et al, 2023;Wichmann et al, 2021). Conceivably, the SOD1 activitiy variabilities might have partially the same background.…”

Section: Sod1 Activity In Csf Of Als Patients and Controlsmentioning

confidence: 99%

SOD1 Enzymatic Activity in CSF from ALS patients with and withoutSOD1mutations

Leykam,

Forsberg,

Nordström

et al. 2024

Preprint

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Superoxide dismutase-1 (SOD1) mutations are a common cause of amyotrophic lateral sclerosis (ALS). Intrathecal gene therapy using the antisense-oligo-nucleotide drug tofersen to reduceSOD1expression shows significant effects on disease progression and has recently been approved in the United States and the European Union. However, the discovery of children homozygous for four different inactivatingSOD1mutations developing the Infantile SOD1 Deficiency Syndrome (ISODDES) with injury to both upper and lower motor systems suggests that low SOD1 activities may be deleterious in humans. Monitoring SOD1 activity in cerebrospinal fluid (CSF) from tofersen-treated patients is advisable but difficult due to low levels and the presence of the isoenzyme SOD3. We here present a method to efficiently remove SOD3 from CSF using highly specific immobilized antibodies and subsequent measurement of the SOD activity as a sensitive assay for the SOD1 activity in CSF. We applied the method on CSF samples from ALS patients and controls and used paired erythrocyte samples for comparison. In ALS patients with wildtypeSOD1,the SOD1 activity in CSF was the same as in controls, but patients with mutantSOD1show lower activity in CSF, even patients with mutants previously reported to have full activity in erythrocytes. Activity variation is large among patients carrying the sameSOD1mutation and larger than seen in erythrocytes and in post-mortem central nervous system tissue. SOD1 in CSF shows a high specific activity, indicating that it is mainly native. Lastly, we identified a discrepancy between the SOD1 activity and protein level measured with ELISA in both CSF and erythrocytes. Since antibodies for SOD1 ELISA-quantification are raised against the native wildtype enzyme, the content of mutant SOD1s may be underestimated. Direct analysis of SOD1 enzymatic activity in CSF is therefore a more reliable way to monitor the effect of SOD1-lowering compounds.

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“…3 Recent population studies in this area have demonstrated that there is a wide variation of CSF protein levels among normal individuals, and it is recommended that reference ranges should become age-adjusted. 5,6 For example, a longitudinal population-based study reported the mean CSF protein level to be 0.52 g/L, significantly higher than the standard reference range (95% reference range of 0.24-0.93 g/L). 6 Factors independently associated with…”

mentioning

confidence: 99%

“…5,6 For example, a longitudinal population-based study reported the mean CSF protein level to be 0.52 g/L, significantly higher than the standard reference range (95% reference range of 0.24-0.93 g/L). 6 Factors independently associated with…”

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confidence: 99%

Cerebrospinal fluid protein: what is a normal reference range?

Tan,

Goh,

Burton

et al. 2023

Internal Medicine Journal

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Population-Based Evaluation of Total Protein in Cerebrospinal Fluid

Cited by 10 publications

References 23 publications

European Stroke Organisation (ESO) guidelines on Primary Angiitis of the Central Nervous System (PACNS)

European Stroke Organisation (ESO) guidelines on Primary Angiitis of the Central Nervous System (PACNS)

SOD1 Enzymatic Activity in CSF from ALS patients with and withoutSOD1mutations

Cerebrospinal fluid protein: what is a normal reference range?

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