Relationship between cerebrospinal fluid/serum albumin quotient and phenotype in amyotrophic lateral sclerosis: a retrospective study on 328 patients

Verde, Federico; Ferrari, Ivan; Maranzano, Alessio; Ciusani, Emilio; Torre, Silvia; Milone, Ilaria; Colombo, Eleonora; Doretti, Alberto; Peverelli, Silvia; Maderna, Luca; Poletti, Barbara; Messina, Stefano; Morelli, Claudia; Silani, Vincenzo; Ticozzi, Nicola

doi:10.1007/s10072-023-06604-3

Cited by 7 publications

(7 citation statements)

References 41 publications

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“…Interestingly, QAlb did not correlate with age at sampling or age of onset in either males or females. This could reflect that an ALS-driven elevation of QAlb would overtake the age-related increase observed in healthy populations, as already discussed [ 22 ]. According to this gender difference, we believe it is crucial to stratify data by sex to understand the implication of BBB/BSCB alteration in ALS.…”

Section: Discussionmentioning

confidence: 75%

“…The results of these studies are weighted by the limited number of patients and the heterogeneity or blur about the timing of QAlb evaluation regarding diagnosis of the disease. A source of the variability reported might be the different upper reference limits of QAlb used [ 18 , 20 , 22 ]. Thus, BBB/BSCB disruption would not appear in all individuals, at least at the time of diagnosis, and this illustrates the complex heterogeneity of ALS and could suggest the involvement of different pathophysiological mechanisms between patients.…”

Section: Discussionmentioning

confidence: 99%

“…Despite its limitations, the albumin quotient (QAlb) is the most commonly used marker for reflecting BBB/BSCB permeability. Elevation in QAlb levels has been reported in 20–50% of ALS patients [ 17 , 18 , 19 ] and its association with the progression of the disease remains controversial [ 18 , 20 , 21 , 22 ]. Moreover, BBB/BSCB impairments have especially been studied in the context of SOD1 mutated models of the disease [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

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Implication of Central Nervous System Barrier Impairment in Amyotrophic Lateral Sclerosis: Gender-Related Difference in Patients

Alarcan

Vourc’h

Berton

et al. 2023

IJMS

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Central nervous system (CNS) barrier impairment has been reported in amyotrophic lateral sclerosis (ALS), highlighting its potential significance in the disease. In this context, we aim to shed light on its involvement in the disease, by determining albumin quotient (QAlb) at the time of diagnosis of ALS in a large cohort of patients. Patients from the university hospital of Tours (n = 307) were included in this monocentric, retrospective study. In total, 92 patients (30%) had elevated QAlb levels. This percentage was higher in males (43%) than in females (15%). Interestingly, QAlb was not associated with age of onset, age at sampling or diagnostic delay. However, we found an association with ALS functional rating scale-revised (ALSFRS-r) at diagnosis but this was significant only in males. The QAlb levels were not linked to the presence of a pathogenic mutation. Finally, we performed a multivariate survival analysis and found that QAlb was significantly associated with survival in male patients (HR = 2.3, 95% CI = 1.2–4.3, p = 0.009). A longitudinal evaluation of markers of barrier impairment, in combination with inflammatory biomarkers, could give insight into the involvement of CNS barrier impairment in the pathogenesis of the disease. The gender difference might guide the development of new drugs and help personalise the treatment of ALS.

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Section: Discussionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Implication of Central Nervous System Barrier Impairment in Amyotrophic Lateral Sclerosis: Gender-Related Difference in Patients

Alarcan

Vourc’h

Berton

et al. 2023

IJMS

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“…We have also found the barrier integrity to be lower in sporadic ALS iBECs as compared to C9orf72 iBECs and accompanied by increased passive permeability to 5 kDa and 150 kDa fluorescent tracers, pointing to potential phenotypic heterogeneity between disease subtypes. This could also explain inconsistent results of clinical reports where BBB disruption was found only in a fraction of ALS patients (82)(83)(84)(85), highlighting the need for more careful patient stratification in generalised cohort studies.…”

Section: Discussionmentioning

confidence: 94%

A patient-derived amyotrophic lateral sclerosis blood-brain barrier cell model reveals focused ultrasound-mediated anti-TDP-43 antibody delivery

Wasielewska,

Castro Cabral-da-Silva,

Pecoraro

et al. 2024

Preprint

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BackgroundAmyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disorder with minimally effective treatment options. An important hurdle in ALS drug development is the non-invasive therapeutic access to the motor cortex currently limited by the presence of the blood-brain barrier (BBB). Focused ultrasound and microbubble (FUS+MB) treatment is an emerging technology that was successfully used in ALS patients to temporarily open the cortical BBB. However, FUS+MB-mediated drug delivery across ALS patients’ BBB has not yet been reported. Similarly, the effects of FUS+MBon human ALS BBB cells remain unexplored.MethodsHere we established the first FUS+MB-compatible, fully-human ALS patient-cell-derived BBB model based on induced brain endothelial-like cells (iBECs) to study anti-TDP-43 antibody delivery and FUS+MBbioeffectsin vitro.ResultsGenerated ALS iBECs recapitulated disease-specific hallmarks of BBB pathology, including changes to BBB integrity, permeability and TDP-43 proteinopathy. Our results also identified differences between sporadic ALS and familial (C9orf72expansion carrying) ALS iBECs reflecting patient heterogeneity associated with disease subgroups. Studies in these models revealed successful ALS iBEC monolayer openingin vitrowith a lack of adverse cellular effects of FUS+MB. This was accompanied by the molecular bioeffects of FUS+MBin ALS iBECs including changes in expression of tight and adherens junction markers, and drug transporter and inflammatory mediators, with sporadic and C9orf72 ALS iBECs generating transient specific responses. Additionally, we demonstrated an effective increase in the delivery of anti-TDP-43 antibody with FUS+MBin C9orf72 (2.7-fold) and sporadic (1.9-fold) ALS iBECs providing the first proof-of-concept evidence that FUS+MBcan be used to enhance the permeability of large molecule therapeutics across the BBB in a human ALSin vitromodel.ConclusionsTogether, our study describes the first characterisation of cellular and molecular responses of ALS iBECs to FUS+MBand provides a fully-human platform for FUS+MB-mediated drug delivery screening on an ALS BBBin vitromodel.

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“…This finding most likely expresses the quantitative interrelation of blood-CSF-barrier dysfunction and severity of disease progression of immune-mediated neuropathies. Interestingly, this correlation has not yet been thoroughly investigated and was only negative in patients with amyotrophic lateral sclerosis ( 30 ).…”

Section: Discussionmentioning

confidence: 99%

Comparative analysis of albumin quotient and total CSF protein in immune-mediated neuropathies: a multicenter study on diagnostic implications

Seeliger,

Gingele,

Güzeloglu

et al. 2024

Front. Neurol.

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IntroductionBlood-cerebrospinal fluid (CSF) barrier dysfunction is pivotal for diagnosing immune-mediated neuropathies, especially in spinal nerve root inflammation. Typically, either total CSF protein or the CSF to serum albumin ratio (QAlb) is measured. Total CSF protein measurements have limitations, notably its fixed reference value regardless of age, in contrast to the age-dependent reference for QAlb. Our goal was to evaluate both markers in patients with immune-mediated neuropathies.MethodsIn our multicenter research, we collected retrospective CSF data from patients suffering from immune-mediated neuropathies across four German research centers. These parameters were analyzed in relation to their clinical characteristics.ResultsOut of 419 samples, 36 (8.6%) displayed a notable variation between total CSF protein and QAlb values. A detailed analysis revealed that patients displaying elevated QAlb but normal total CSF protein levels were significantly younger at disease onset (p = 0.01), at the time of diagnosis (p = 0.005), and when undergoing lumbar puncture (p = 0.001) compared to patients with elevated CSF protein and normal QAlb levels. These effects were especially evident for the subgroup of samples derived by female patients.DiscussionOur work confirms the crucial role of QAlb in diagnosing immune-mediated neuropathies and particularly its efficacy as a marker for evaluating the blood-CSF barrier in patients with an earlier disease onset. Considering the significance of the albumin quotient, its assessment is especially advisable in younger patients of female sex to avoid missing a potential barrier dysfunction that might be falsely negative when using total protein.

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Relationship between cerebrospinal fluid/serum albumin quotient and phenotype in amyotrophic lateral sclerosis: a retrospective study on 328 patients

Cited by 7 publications

References 41 publications

Implication of Central Nervous System Barrier Impairment in Amyotrophic Lateral Sclerosis: Gender-Related Difference in Patients

Implication of Central Nervous System Barrier Impairment in Amyotrophic Lateral Sclerosis: Gender-Related Difference in Patients

A patient-derived amyotrophic lateral sclerosis blood-brain barrier cell model reveals focused ultrasound-mediated anti-TDP-43 antibody delivery

Comparative analysis of albumin quotient and total CSF protein in immune-mediated neuropathies: a multicenter study on diagnostic implications

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