Cerebral amyloid angiopathy (CAA) is caused by the accumulation of amyloid-beta (Aβ) in the cerebrovasculature. The glymphatic system is thought to be involved in the clearance of cerebral waste products, including Aβ. Stimulation of the glymphatic system through enhancing deep sleep with low-sodium oxybate (LXB) or inhibition of cortical spreading depolarisations via non-invasive vagus nerve stimulation (nVNS) could potentially increase clearance of Aβ and hence improve disease course.

We will perform a pre-post trial to assess whether treatment with LXB, nVNS or a combination of both interventions can enhance the clearance of Aβ in patients with CAA. A total of 60 participants, 30 with sporadic CAA and 30 with Dutch-type CAA, will be randomly assigned to receive either LXB, nVNS or both interventions, resulting in three groups (20 in each group: LXB, nVNS and both). The study spans 6 months, comprising a 3-month observational phase and a 3-month intervention phase. The primary outcome measure will be the morning levels of Aβ40 and Aβ42 in cerebrospinal fluid (CSF) before and after the intervention. We will assess possible disease progression with (non-)haemorrhagic imaging markers on 7-Tesla MRI at baseline, before and after intervention, as a secondary outcome. Additionally, the activity of the glymphatic system by means of fluid dynamics will be assessed with CSF-Selective T2-weighted Readout with Acceleration and Mobility encoding (CSF-STREAM) on 7-Tesla MRI.

The study was reviewed and approved by the Medical Research Ethics Committee Leiden The Hague Delft (P23.100) on 8 April 2024. The first participant was enrolled on 27 March 2025. Study results will be published in peer-reviewed journals and presented at scientific conferences. Additionally, study updates and results will be shared with participants via our newsletter twice a year.

EU CT number 2023–5 06 128-10-00, Universal Trial Number U1111-1295-1113, ClinicalTrials.gov NCT06421532.

Frontotemporal lobar degeneration (FTLD) is the second most common early-onset dementia. Several studies demonstrated that neuroinflammation and iron accumulation occur in FTLD. However, the timing and relevance of these processes and whether these two are merely cause or consequence remains unclear. Elucidating the role is crucial to assess the rationale for using anti-inflammatory therapies in FTLD. Additionally, the process of glymphatic brain clearance has gained attention as a potential contributor in the disease pathophysiology.

In this multimodal biomarker study, we use a combination of ultra-high field (7T) MR, blood and cerebrospinal fluid (CSF) biomarkers to investigate the role of neuroinflammation, iron accumulation and brain clearance in FTLD, and to identify biomarkers to differentiate FTLD-TDP from FTLD-tau. We aim to include 25 patients with probable FTLD-tau, 25 with probable FTLD-TDP and 50 healthy individuals with 50% risk to develop FTLD. We will use several MRI techniques, including magnetic resonance spectroscopy, diffusion weighted spectroscopy and quantitative susceptibility mapping. In addition, we will assess the prevalence of perivascular spaces (PVS) and the mobility of CSF to address glymphatic brain clearance. We will compare quantitative MR markers between patients with FTLD-tau and FTLD-TDP, presymptomatic mutation carriers and healthy controls, and correlate these measures with clinical data and biomarkers in blood and CSF.

We obtained ethical approval from the Medical Ethics Committee Leiden Den Haag Delft (NL78272.058.21). The results will be disseminated through presentations at national and international conferences, open-access peer-reviewed publications, ClinicalTrials.gov and to the public through social media posts and annual newsletters.

NCT06870838; Pre-results.