Using PET-imaging to detect cortical synapse loss in multiple sclerosis

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In Germany, around 250,000 people suffer from multiple sclerosis, or MS for short. It is an autoimmune disease in which the body's immune system attacks structures in the central nervous system. The attacks also lead to changes in the grey matter in the brain – the mass of nerve cell bodies and nerve cell connections (synapses) that form our ‘computing center’.

Until now, there has been no reliable and meaningful method of detecting these pathological lesions in the grey matter. Now, however, researchers at LMU Hospital have shown for the first time that positron emission tomography (PET) can be used to image synapse loss in MS lesions in the cerebral cortex. In the long term, the researchers led by Prof Matthias Brendel (Clinic and Polyclinic for Nuclear Medicine) and Prof Martin Kerschensteiner (Institute for Clinical Neuroimmunology and Spokesperson BMC) want to develop the procedure ‘so that we can use it to guide therapy,’ as Brendel says.

In MS, the destruction of the covering of the nerve endings and the nerve cells themselves causes symptoms that affect all brain and spinal cord functions. These include blurred vision, double vision, visual field defects, tingling, numbness, pins and needles in the arms or legs, muscle weakness, unsteady gait, spasticity, muscle cramps, pronounced physical and mental fatigue after minor exertion (fatigue), coordination disorders and dizziness, urinary urgency, incontinence, constipation, libido or erectile dysfunction, as well as concentration disorders, memory loss, depression or mood swings.

According to Martin Kerschensteiner, recent studies increasingly show that pathological changes in grey matter are decisive for the progression of the disease, especially for permanent disability, cognitive impairment and persistent fatigue. Furthermore, lesions in the grey matter predict the risk of deterioration and the transition from a relapsing-remitting to a permanently progressive disease. The problem is that magnetic resonance imaging (MRI), which is commonly used for diagnosis, is unable to diagnostically visualise most changes in the grey matter.

Can another imaging technique, like PET, help? To do so, it would be necessary to find a protein in the nerve cells that can be detected using this technique and that also provides valuable information about the density of the neurons and their synapses. In a series of experiments, the Kerschensteiner laboratory first demonstrated that the protein SV2A is a suitable marker for synapse density in MS. The team then injected mice with MS-like inflammation of the cerebral cortex with a weakly radioactive substance that specifically binds to SV2A. The radioactive signal is then detected by the PET scanner. For control and comparison purposes, the synapse densities in the same lesions were measured using established methods. ‘This enabled us to show that the synapse densities measured with PET imaging produce meaningful results,’ explains Kerschensteiner, ‘which was also confirmed in a subsequent study involving more than 30 MS patients.’

The researchers now have a clear goal: ‘We want to use this to guide treatment,’ says Brendel. ‘The idea is to identify patients at high risk of disease progression and to target them with treatment that specifically addresses the progression of the disease.’ To this end, the next step is to launch long-term observation studies to investigate whether and how well the long-term course of the disease can be predicted with a single PET scan.

Publication: Ullrich Gavilanes EM et al.: SV2A-PET imaging uncovers cortical synapse loss in multiple sclerosis. Sci Transl Med. 2025 Oct

Source: LMU Klinik