RPS 1711 - CSF, glymphatic system and MR contrast agents

Author Block: K. Deike, A. Radbruch, G. Petzold; Bonn/DE
Purpose: Impaired perivascular clearance is a critical step in the pathogenesis of cerebral amyloid angiopathy (CAA), which is characterized by amyloid-beta accumulation in cerebral vessels. However, only few brain clearance imaging techniques are available that can be applied non-invasively in humans and the majority of assessed parameters is of indirect and/or semi-quantitative nature. Therefore, this study aimed to quantifiy the cerebrospinal fluid (CSF) mobility in the PVS of CAA patients and healthy controls (HC).
Methods or Background: To assess perivascular CSF mobility, we applied a specifically for this task developed 7-Tesla MRI sequence for the first time in patients with a diagnosed brain clearance disorder. The CSF mobility maps of 8 CAA patients (according to Boston criteria 2.0) and 9 HCs were used to semi-automatically segment the PVS in the centrum semiovale (CSO) and to calculate the CSF flow within the PVS.
Results or Findings: The CAA and HC group did not differ significantly in terms of age and gender. However, CAA patients depicted a significantly higher PVS volume in the CSO compared to HC (p < 0.01). CSF mobility correlated negatively with PVS size in both groups (p < 0.01), which is in accordance with expectations from fluid dynamics. While absolute CSF mobility did not differ significantly between both groups, CAA patients revealed a significantly lower decrease in CSF mobility with increasing PVS size compared to HC (p < 0.05).
Conclusion: This study is the first providing proof of concept for clinical usage of brain clearance imaging with non-invasive CSF mobility mapping in humans and revealed altered brain clearance in enlarged PVS of CAA patients.
Limitations: CSF mobility measurements do not allow to draw conclusions on net CSF flow, flow direction or overall clearance capacity.
Funding for this study: This work was supported by the EU Joint Programme for Neurodegenerative Disease Research (JPND) and the Fondation Leducq (Transatlantic Network of Excellence 23CVD03).
Has your study been approved by an ethics committee? Yes
Ethics committee - additional information: Number 437/21

Author Block: F. M. Doniselli, A. Gans, M. A. Broggi, V. Redaelli, M. Moscatelli, M. Verri, D. Aquino, R. Pascuzzo, M. Grisoli; Milan/IT
Purpose: Idiopathic normal-pressure hydrocephalus (iNPH) is a neurodegenerative disorder present in more than 5% of the population over 80 years of age, and the treatment of choice is ventriculoperitoneal (VP) shunt surgery. Assessment of high-volume lumbar tap test (LTT) has sufficiently high positive predictive values to predict VP response. Radiologic signs of iNPH (Evans index, transcallosal angle, and disproportionately dilated subarachnoid space (DESH)) provide diagnostic morphologic features but are not predictive of response to surgery. More recent etiologic hypotheses of iNPH include a dysfunction of the glymphatic system (GS). DTI imaging targeting perivascular spaces (DTI-ALPS) has shown the presence of reduced perivascular diffusivity in iNPH patients, an indirect index of GS dysfunction. The purpose of our work is to evaluate DTI-ALPS as a predictor of VP response.
Methods or Background: Between 2021 and 2023, 89 patients diagnosed with probable iNPH underwent LTT testing. Of these, 22 were enrolled in the study with pre- and post-LTT DTI-ALPS sequences. Fifteen patients responded positively to LTT test and 14 of them underwent VP. Among the 14 patients who underwent VP, 9 underwent 3-month MR follow-up. 7 healthy patients were included as a control group.
Results or Findings: 68% (15/22) of patients responded positively to LTT; of these 93% (14/15) underwent VP surgery with clinical benefit in 86% (12/14). The ALPS index in controls was higher than in iNPH patients (P <0.01). The ALPS index pre-LTT (T0) was significantly higher in LTT-responsive patients (P <0.01). The ALPS index (T0) correlated with clinical indices (P <0.01), and these were significantly improved at T3 (P <0.05).
Conclusion: ALPS index provides a noninvasive, reproducible, and reliable diagnostic and prognostic tool in the evaluation of the iNPH patient that can significantly improve surgical selection.
Limitations: There was only a small cohort of patients and this was a single-centre study.
Funding for this study: This study received no funding.
Has your study been approved by an ethics committee? Yes
Ethics committee - additional information: This study was approved by the internal ethics committee.

Author Block: A. Pichiecchio¹, L. Loevner², G. Hutóczki³, K. Dziadziuszko⁴, C. Groden⁵, C. Oppenheim⁶, L. M. Farina⁷; ¹Borgarello/IT, ²Philadelphia, PA/US, ³Debrecen/HU, ⁴Gdańsk/PL, ⁵Mannheim/DE, ⁶Paris/FR, ⁷Pavia/IT
Purpose: Gadopiclenol (Elucirem™, Guerbet) is a high relaxivity macrocyclic gadolinium-based contrast agent (GBCA), approved by the FDA and currently under review by the EMA. This study aimed to compare contrast-enhanced MRI with gadopiclenol at 0.05 mmol/kg and gadobutrol at 0.1 mmol/kg in terms of visualisation of brain metastases.
Methods or Background: This is a post hoc analysis of the phase III PICTURE (gadoPIClenol for cenTral nervoUs system magnetic REsonance) study. A subpopulation of patients with brain metastases (N=46) who underwent two separate MRIs with gadopiclenol and gadobutrol was analysed. Lesion visualisation parameters (border delineation, internal morphology and contrast enhancement) were assessed by three off-site blinded readers. Percentage of enhancement (E%), lesion to background ratio (LBR) and contrast to noise ratio (CNR) were measured. Overall diagnostic preference was assessed in a global matched pairs fashion by three additional blinded readers.
Results or Findings: For all readers, and all visualisation parameters, the difference in mean of scores showed the non-inferiority of gadopiclenol to gadobutrol (lower limit of 95% CI between -0.04 and -0.30 depending on the reader, above the non-inferiority margin [‑0.35]).
There was no significant difference between the two GBCAs in terms of CNR, while a higher E% was observed with gadopiclenol for two of three readers (P ≤0.0097), and a higher LBR for the three readers (P ≤0.0036). Readers preferred images with gadopiclenol in 54% to 59% of evaluations, reported no preference for 13% to 24% of evaluations, and preferred images with gadobutrol in 22% to 30% of evaluations.
Conclusion: MRI with gadopiclenol at 0.05 mmol/kg is non-inferior to gadobutrol at 0.1 mmol/kg for brain metastases visualisation.
Limitations: This is a post-hoc analysis with a limited number of patients.
Funding for this study: This study was sponsored by Guerbet.
Has your study been approved by an ethics committee? Not applicable
Ethics committee - additional information: As a post-hoc analysis, this study did not require ethics committee approval.

Author Block: A. Treu¹, J. Boyken², J. Lohrke², G. Jost², U. Thuss¹, H. Pietsch²; ¹Wuppertal/DE, ²Berlin/DE
Purpose: Gadolinium presence in the body has triggered intense research in recent years. Most preclinical studies determined the overall Gd concentrations, this study investigated the distribution and chemical form of the applied GBCAs in the skin using matrix-assisted laser desorption/ionisation mass spectrometry imaging (MALDI MSI).
Methods or Background: Rats received either a single (1x0.6 mmol/kg) or multiple intravenous injections within 2 weeks (8x0.6 mmol/kg) of gadobutrol or saline. The Gd distribution and concentration in skin after multiple injections were measured after 5 days and 5 weeks by inductively coupled plasma-mass spectrometry (ICP-MS) and laser ablation-ICP-MS (LA-ICP-MS). The intact gadobutrol in the skin (MW 604.72 g/mol) was determined with MALDI MSI 5 days (multiple dose) and 1 week post injection (single dose). Neodymium- or holmium-butrol was used as internal standard for quantification in MALDI MSI.
Results or Findings: Total gadolinium skin concentration measured by ICP-MS at 5 days after 8x0.6 mmol/kg for gadobutrol was 2.7±1.1 nmol/g. Importantly, gadobutrol was detected within the dermis as intact Gd-chelate using MALDI MSI. There were no indications for dechelation, as the Gd quantification and distribution by LA-ICP-MS was very similar with the intact gadobutrol detected by MALDI MSI. Intact gadobutrol was predominantly detected in the sweat glands with an average of 4.1±1.1 compared to 5.0±1.2 nmol/g total gadolinium measured by LA-ICP-MS.
Conclusion: MALDI MSI showed the chemical form of residual gadolinium being intact Gd-chelate. No indications for dechelation of free gadolinium were observed. Gadobutrol levels in the skin measured as total gadolinium via LA-ICP-MS were low and almost completely eliminated within 5 weeks. After 5 days, intact Gd-chelate was localised in sweat glands, suggesting a potential elimination route via sweat.
Limitations: There are species differences in terms of skin physiology between rats and humans.
Funding for this study: All authors were Bayer AG employees.
Has your study been approved by an ethics committee? Yes
Ethics committee - additional information: LaGeSo Berlin approved this study (approval for in vivo studies).

Author Block: L-P. Schmill, S. Seehafer, S. Aludin, N. Larsen, O. Jansen; Kiel/DE
Purpose: After angiographic thrombectomy in acute stroke with partial cerebral infarction, gadolinium-based contrast agents (GBCA) are rarely detected in the cerebrospinal fluid (CSF) on T1-weighted sequences. Such disruptions of the blood-CSF and brain-CSF barriers would in principle also be expected in inflammatory or tumour diseases, although they have not yet been observed and further studied. In order to make the detection of gadolinium as sensitive as possible and to be able to detect a deviation from the appropriate inversion time of the CSF with only small amounts of gadolinium, we have modified the fluid-attenuated inversion recovery (FLAIR) technique.
Methods or Background: A MRI phantom was prepared using a series of dilutions of GBCA in isotonic saline (1:250; 1:500; 1:1,000; 1:2,000; 1:4,000; 1:8,000; 1:16,000; 1:32,000; 1:64,000; 1:128,000; 1:256,000) and native controls of pure isotonic saline. Around the test tubes, the phantom was filled with agarose gel with the addition of MnCl2 (0.08 mmol/l) to match MRI tissue properties of the brain parenchyma. A 3T MRI (Magnetom, Vida, Germany) was subsequently used to test the FLAIR sequence with different parameters of TR, TE and TI in order to obtain the most complete suppression of isotonic saline and agarose gel while allowing high sensitivity for the contrast agent contained.
Results or Findings: Optimal detection of gadolinium at a dilution of 1:256,000 was possible using a FLAIR with a TR of 9,000 ms, a TI of 1,800 ms and a TE of 650 ms. The signal intensity ratio of sample (44 SI) to isotonic saline (17 SI) was 2.59.
Conclusion: The highly T2-weighted FLAIR sequence is excellent for the detection of subtle amounts of contrast agent in the CSF.
Limitations: This study lacked translation to clinical examinations.
Funding for this study: No funding was received for this study.
Has your study been approved by an ethics committee? Yes
Ethics committee - additional information: The study was approved by the institutional review board and written informed consent was obtained from all participants.

Author Block: B. M. Hofmann¹, G. Sutter¹, T. Fadini¹, S. Klein¹, E. Vendel², P. Vis², S. Heitmeier³, T. Frenzel¹, W. Ebert¹; ¹Berlin/DE, ²Leiden/NL, ³Wuppertal/DE
Purpose: The aim of this study was to evaluate the pharmacokinetics (PK) and safety of the novel, tetrameric macrocyclic gadolinium-based contrast agent (GBCA) gadoquatrane, using clinical trial data with modeling & simulation (M&S) approaches and in vitro testing for dialysability assessment, leveraging the broad knowledge of the class of GBCAs avoiding exposure of vulnerable patient populations, i.e. with severe renal impairment or ESRD, in clinical trials.
Methods or Background: An open-label, single-dose phase 1 study investigated PK (plasma PK, excretion until 7 days p.i. and up to 6 months p.i.) and safety in adult participants (8 per group, dose: 0.025mmol/kg, i.e. 0.1mmol Gd/kg): 1) Mildly impaired renal function (RF) (eGFR: 60-89mL/min/1.73m2), 2) Moderately impaired RF (eGFR: 30-59mL/min/1.73m2) 3) matched controls (normal RF: eGFR: ≥90mL/min/1.73m2). PK in patients with severely impaired RF (eGFR<30mL/min/1.73m2) was simulated using an established popPK model. Dialysability of gadoquatrane was investigated in human blood using a clinical dialysis system versus gadobutrol.
Results or Findings: Similar Cmax and volume of distribution (Vss/BW) independent of renal function were observed. Systemic exposure (AUC) increased and CL/BW decreased with increasing renal impairment. Within the 7 days collection interval, gadoquatrane excretion was essentially complete in all groups. Late measurements with a highly sensitive LLOQ confirmed continuous excretion of trace amounts. Gadoquatrane was safe and well tolerated in all groups. Simulated plasma PK in severely impaired patients showed expected further increase of AUC and decrease of CL/BW according to renal function. In vitro investigations confirmed dialysability of gadoquatrane as known for gadobutrol.
Conclusion: Gadoquatrane displays expected PK and safety in mild and moderate renal impairment versus matched controls. Simulation of PK in severe renal impairment and in vitro testing of dialysability allowed avoiding exposure of vulnerable patient populations in clinical trials.
Limitations: The number of participants with RF in the clinical study was limited.
Funding for this study: This study received funding from the Bayer AG.
Has your study been approved by an ethics committee? Yes
Ethics committee - additional information: The study protocol was reviewed and approved by each of the two study site's IEC/IRB before the start of the study.