The Leuven late life depression (L3D) study: PET-MRI biomarkers of pathological brain ageing in late-life depression: study protocol

Louise Emsell, Maarten Laroy, Margot Van Cauwenberge, Thomas Vande Casteele, Kristof Vansteelandt, Koen Van Laere, Stefan Sunaert, Jan Van den Stock, Filip Bouckaert, Mathieu Vandenbulcke, Louise Emsell, Maarten Laroy, Margot Van Cauwenberge, Thomas Vande Casteele, Kristof Vansteelandt, Koen Van Laere, Stefan Sunaert, Jan Van den Stock, Filip Bouckaert, Mathieu Vandenbulcke

Abstract

Background: Major depressive disorders rank in the top ten causes of ill health in all but four countries worldwide and are the leading cause of years lived with disability in Europe (WHO). Recent research suggests that neurodegenerative pathology may contribute to the development of late-life depression (LLD) in a sub-group of patients and represent a target for prevention and early diagnosis. In parallel, electroconvulsive therapy (ECT), which is the most effective treatment for severe LLD, has been associated with significant brain structural changes. In both LLD and ECT hippocampal volume change plays a central role; however, the neurobiological mechanism underlying it and its relevance for clinical outcomes remain unresolved.

Methods: This is a monocentric, clinical cohort study with a cross-sectional arm evaluating PET-MR imaging and behavioural measures in 64 patients with LLD compared to 64 healthy controls, and a longitudinal arm evaluating the same imaging and behavioural measures after 10 ECT sessions in 20 patients receiving ECT as part of their normal clinical management. Triple tracer PET-MRI data will be used to measure: hippocampal volume (high resolution MRI), synaptic density using [11C]UCB-J, which targets the Synaptic Vesicle Glycoprotein 2A receptor, tau pathology using [18F]MK-6240, and cerebral amyloid using [18F]-Flutemetamol, which targets beta-amyloid neuritic plaques in the brain. Additional MRI measures and ultrasound will assess cerebral vascular structure and brain connectivity. Formal clinical and neuropsychological assessments will be conducted alongside experience sampling and physiological monitoring to assess mood, stress, cognition and psychomotor function.

Discussion: The main aim of the study is to identify the origin and consequences of hippocampal volume differences in LLD by investigating how biomarkers of pathological ageing contribute to medial temporal lobe pathology. Studying how synaptic density, tau, amyloid and vascular pathology relate to neuropsychological, psychomotor function, stress and ECT, will increase our pathophysiological understanding of the in vivo molecular, structural and functional alterations occurring in depression and what effect this has on clinical outcome. It may also lead to improvements in the differential diagnosis of depression and dementia yielding earlier, more optimal, cost-effective clinical management. Finally, it will improve our understanding of the neurobiological mechanism of ECT.

Trial registration: ClinicalTrials.gov Identifier: NCT03849417 , 21/2/2019.

Keywords: Ageing; Amyloid; Brain; ECT; Late life depression; MRI; Neurodegeneration; PET; Synaptic density; Tau.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Schematic timeline for L3D data collection. Figure legend: amy: Amyloid PET, blood: blood sampling (apolipoprotein □4 genotyping, blood glucose and serum lipids), CB: Chill Band wristband monitoring, CON: control subject, ECT: electroconvulsive therapy, EMA: ecological momentary assessment, LLD: late-life depression, MRI: magnetic resonance imaging, motor: neurological and task based assessment of motor function, NP: neuropsychological testing and psychiatric intake, SV2A: synaptic density PET with synaptic vesicle 2A tracer, t:tau PET, US: doppler ultrasound (intima media thickness) *following the 10th ECT treatment

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