New Eyes on the Brain: Inside KU Leuven's NeuroEXPLORER Revolution

What changes most drastically is our ability to resolve small brain structures and visualize them as distinct entities, rather than as a blurred or mixed signal of neighbouring regions. This high level of detail allows us not only to visualize but also to reliably quantify PET tracer binding in small brain structures that are critically involved in neurodegeneration, but which were indistinguishable on scans from standard-of-care PET systems.

These include brainstem nuclei such as the substantia nigra and locus coeruleus, small regions that play important roles in the onset of Parkinson's disease and Alzheimer's disease, respectively. Next to the visualization of small brain nuclei that were previously invisible, the NeuroEXPLORER also achieves a much sharper delineation of the large cortical grey matter in the brain, and the system has a much higher sensitivity compared to standard-of-care PET systems. This will result in overall more accurate quantifications of PET tracer binding in the brain, which might enable an earlier detection of very small changes that occur in neurodegenerative disorders.

One of the greatest challenges in neurodegenerative diseases is that by the time symptoms become clinically obvious, substantial and often irreversible brain damage has already occurred. The NeuroEXPLORER gives us the opportunity to study the earliest molecular changes that precede these symptoms.

In Parkinson's disease, for example, the degeneration is thought not to begin uniformly across the brain but in very small brain structures (the substantia nigra) and specific circuits (dopaminergic neurotransmission). With ultra-high-resolution PET, we can begin to study these small regions and circuits in vivo — potentially leading to the differentiation of subtypes based on their molecular signature.

This opens the door to precision diagnosis: matching patients to therapies based on what is actually happening in their brain, rather than applying a one-size-fits-all approach. For atypical parkinsonian disorders, where clinical diagnosis is particularly challenging, improved molecular specificity could significantly reduce misdiagnosis and help guide more appropriate treatment decisions much earlier.

For dementia, a specific circuit in the brain that is thought to be crucial for memory consolidation, called the Papez circuit and which consists of very small brain nuclei, can now be studied. This will allow us to investigate its importance in vivo and throughout the course of clinical disease progression.

Yes, I believe it could. One of the bottlenecks in developing new medicines is the lack of sensitive, reliable biomarkers that can detect small changes within the relatively short timescale of a clinical trial. If the biomarker isn't sensitive to subtle treatment effects, then promising therapies may appear ineffective because we lack the sensitivity to measure their impact.

The NeuroEXPLORER not only achieves a much better resolution, but it also has a very high effective sensitivity. This sensitivity allows us to track small but potentially biologically meaningful molecular changes over time — whether in receptor density, neurotransmitter dynamics, or pathological protein burden. This is particularly valuable in early-phase trials, where patient numbers are small and effect sizes may still be modest.

Neurotransmitter systems that originate in small brain nuclei will benefit the most. These include the dopaminergic, serotonergic, cholinergic, and noradrenergic systems. They all have highly specific projection patterns as well. Historically, PET imaging of these systems has been limited by the low spatial resolution, but ultra-high-resolution PET with the NeuroEXPLORER allows us to study these nuclei individually rather than as a blurred or mixed signal.

The first image of dopamine transporter PET on the NeuroEXPLORER in a healthy volunteer clearly visualised a high binding in the anteroventral nucleus of the thalamus (see Volpi et al., European Journal of Nuclear Medicine and Molecular Imaging, 2025). This means that we are now able to investigate the importance of this thalamic nucleus in Parkinson's disease as well. This new system opens questions about how different neurotransmitter systems interact, how they degenerate selectively in different diseases, and how compensatory mechanisms may operate in early disease stages. Beyond neurodegeneration, this also has implications for psychiatric disorders, where subtle dysregulation may drive symptoms.

At this level of spatial resolution, motion becomes much more important. Even very small head movements of a few millimetres can significantly degrade the image quality. As a result, advanced motion tracking and correction algorithms become essential. The NeuroEXPLORER integrates continuous head motion tracking so that an event-by-event motion correction can be applied.

AI and machine-learning techniques are increasingly important at multiple stages of the pipeline: from image reconstruction and denoising, to segmentation, pattern recognition, and multimodal data integration also with MRI acquisitions.

There are several hurdles. First, these systems are currently expensive and technically complex, which limits widespread deployment. Second, the data volume and analytical expertise required are far beyond what most clinical imaging departments are set up to handle today. There are also regulatory considerations, as any new diagnostic tool must demonstrate clear clinical benefit and robustness across populations and sites.

Also, devices intended for clinical use in the EU require CE marking, which certifies compliance with applicable EU safety and performance standards. Currently, the NeuroEXPLORER is not CE marked, nor is it FDA-approved for clinical diagnosis. The Leuven system, operational since mid-September 2025, has obtained EU Medical Device Regulation clearance for clinical investigations (EUDAMED CIV-25-06-053398). The safety and efficacy objectives will include registration of Adverse Device Defects and Device Deficiencies, while efficacy will be defined in terms of stable physical performance and prospective clinical (diagnostic) and research evaluations ranging from applications in neurodegeneration, epilepsy, brain tumours, and head-neck applications. With this study, we aim to conduct the initial necessary investigations so that this scanner might eventually be used in routine clinical care.

By enabling direct, in vivo measurement of molecular changes in small but critical brain structures, ultra-high-resolution PET could allow us to study disease mechanisms at the scale where they begin. Within the next decade, this will most likely lead to better disease understanding and possibly also to earlier detection, more accurate disease differentiation and eventually to better-targeted interventions.

As written by the head of the Nuclear Medicine Department at KU Leuven: the NeuroEXPLORER could represent a change in perspective and gives us “new eyes” to study the human brain. This scanner could fundamentally change how we think about disease prevention, monitoring, and intervention.