Toward new frontiers : Encounter and synergy of state-of-the-art astronomical detectors and exotic quantum beams

Program C01-3	Towards a new methodology of functional imaging for the central lymphatic system using an ultra-high-resolution SPECT
Principal Investigator	MIZUMA, Hiroshi (RIKEN)

Immunity is the ability of the host to defend the body from external invasions such as allergens and bacterial and viral infections. The body's immune system responds to resist these invasions. Immune cells play a key role in our body's protection. These cells mature in the bone marrow and in the thymus, reaching the entire body via the blood and lymphatic circulatory systems. The neuro-immune system is known to have unique properties that are unlike the immune system in other peripheral tissues. The neuro-immune system protects the brain by restricting the passage of many molecules and cells between blood vessels and brain parenchyma (blood-brain barrier). For centuries, it was thought that the neuro-immune system lacked lymphatic vessels.

Using advanced fluorescent microscopic techniques, scientists recently discovered lymphatic vessels in rodent and human meninges. This discovery may open a new era, where additional research will add to our understanding of the neuro-immune system. To date, studies have revealed that the brain's lymphatic vessels play important roles in both draining waste generated by neural activities and interacting peripheral immune cells into brain parenchyma. Changes in the brain's lymphatic system may be closely related to aging and pathophysiological states, in particular, Alzheimer's disease and multiple sclerosis.

The structural and functional properties of the brain's lymphatic vessels have gradually been characterized. Yet, a way to systematically visualize the central nervous system (CNS) lymphatic vessels in live state has not been established. In this study, we will develop a newer methodology for functional imaging of the CNS lymphatic system using our in vivo imaging techniques on small animals. To realize this, we will use single-photon emission computed tomography (SPECT) with cadmium telluride (CdTe) detectors. This technique had the potential to produce ultra-high spatial resolution (≲100 μm) based on the cutting-edge technologies for observing X- and gamma-rays in the universe. To visualize the CNS lymphatic kinetics, we will test several SPECT tracers which are radiolabeled to the macromolecules (e.g., ovalbumin) and T cells using Indium-111 (In-111), Gallium-67 (Ga-67), or Technetium-99m (Tc-99m).

By using our developed method, we will make a proposal for innovative therapeutic strategies and/or diagnostic tools for neurologic disorders and brain tumors associated with the dysfunction of the neuro-immune system.

The schema of the CNS lymphatic tracts in a mouse (left). The structural characterizations of CNS lymphatic vessels have been revealed using advanced optical imaging techniques. To visualize the brain’s lymphatic circulation, we use an ultra-high-resolution SPECT scanner with radiolabeled macromolecules and immune cells (right).

Members

Reference Materials

• H. Mizuma et al., “Establishment of in vivo brain imaging method in mice under conscious condition,” J. Nucl. Med. 51, 1068–1075 (2010).
• T. Kambe et al., “Differential regional distribution of phosphorylated tau and synapse loss in the nucleus accumbens in tauopathy model mice,” Neurobiol. Dis. 42, 404–414 (2011).
• Y. Hara et al., “Involvement of the septo-hippocampal cholinergic pathway in association with septal acetylcholinesterase upregulation in a mouse model of tauopathy,” Curr. Alzheimer Res. 14, 94–103 (2017).
• N. Nakai et al., “Serotonin rebalances cortical tuning and behavior linked to autism symptoms in 15q11-13 CNV mice,” Sci. Adv. 3, e1603001 (2017).