New insights into the mechanisms of “Niemann-Pick type C” in children

In the journal “Science Translational Medicine“, scientists from DZNE and LMU Hospital report on new insights into the mechanisms of “Niemann-Pick type C” (NPC), a rare neurodegenerative disease associated with dementia that can manifest as early as childhood. Their findings, based on studies in mice, cell cultures and patients, emphasize that neuroinflammation, which is mediated by the brain’s immune system, plays a crucial role in NPC. In addition, their research points to a biomarker that could potentially be useful in disease monitoring and assessment of treatment response. Specifically, this refers to a molecule called TSPO, which can be detected in the brain by means of positron emission tomography (PET).

We typically associate dementia with elderly people. However, there are also dementias that manifest in children and lead to death already by the age of 30 or even earlier, such as Niemann-Pick type C.”

Dr. Sabina Tahirovic, neuroscientist at DZNE’s Munich site

It is estimated that in Germany around 150 individuals are affected by this rare neurodegenerative disease. They have mutations in one of two specific genes that regulate lipid metabolism. This results in a harmful build-up of fat molecules in the brain and other organs. This, in turn, can trigger movement disorders as well as severe psychiatric and neurological symptoms, including dementia.

Biomarkers needed

“It often takes years before NPC is diagnosed, with multiple visits to different doctors. The critical mutations are easy to detect, but NPC is often not considered initially because the disease is so rare”, Tahirovic explains. Certain drugs acting upon lipid metabolism can alleviate symptoms. However, so far, there are no therapies that can permanently halt the disease. “Although we know the genetic causes of NPC, the mechanisms relevant for its development are still poorly understood. Our results now underscore that neuroinflammation is a decisive factor in NPC. Besides, we identified TSPO as a potential biomarker for disease monitoring and response to therapy,” the neuroscientist says. “With the development of recent therapeutics for NPC, we urgently need such biomarkers to monitor clinical benefits and disease progression.”

A pathological cascade

Building on results from previous studies, Tahirovic and colleagues focused on the “microglia”: these cells belong to the brain’s immune system and are therefore specialized in combating pathogens and other threats. In NPC however, they seem to do more harm than good. “We were able to show that the microglia actively contribute to NPC pathology by triggering a harmful neuroinflammatory response in the brain”, Tahirovic says. “Overall, we see these immune cells as part of a pathological cascade that also involves other brain cells and ultimately leads to neuronal damage. Current treatments for NPC aim to reduce the amount of lipids in cells, as their overload is pathological. Our findings emphasize the significance of inflammation in NPC. In view of this, I believe that combining lipid lowering strategies with immunomodulation is a promising approach for future therapies.”

A potential biomarker

The current research combines studies in mice and cell cultures with the analysis of blood samples and PET scans taken from NPC patients. This was possible through a cooperation with the Department of Nuclear Medicine and the Department of Neurology at the LMU Hospital in Munich. “The so-called translocator protein, or TSPO for short, is a common marker for inflammation in several brain diseases. However, until now, TSPO had not been associated with microglial activation and disease progression in NPC. Specifically, we have found that microglial hyperactivity as observed in NPC is reflected in a marked increase in TSPO levels. As this molecule is found in the power plants of every cell, it apparently comes into play when the microglial energy demand rise,” Tahirovic explains. “Thus, TSPO may serve as a marker for disease monitoring. That is, it could help evaluate the state of the disease and predict its further progression.” In addition, TSPO may also be useful for assessing response to therapy. “We conclude this from data of patients treated with a drug that can alleviate symptoms of NPC. This compound, called N-acetyl-L-Leucine, was recently approved by the US authorities for the treatment of NPC”, Tahirovic says. “In my view TSPO would be a valuable addition to the set of biomarkers that are currently used in other, more common neurodegenerative diseases. It would make sense to combine them and test their utility in clinical trials on NPC.”

PET and blood

TSPO can be imaged in the brain using PET scanning, a technique that is available in specialized clinics and molecular imaging facilities. “TSPO could be of relevance both for clinical studies on NPC as for clinical routine. PET imaging might be difficult with young patients, as they need to stay calm while in the scanner. But we showed that it is feasible with older individuals affected by NPC,” says Prof. Matthias Brendel, a neuroimaging expert at LMU Hospital. Furthermore, data from the current and previous studies suggest that certain blood cells reflect features of the microglia. Specifically, this concerns the macrophages which are, so to speak, siblings of the microglia. “Blood macrophages could also be a way to assess TSPO. Our current assays to monitor TSPO may still be too complex for clinical routine, but there is certainly room for development,” Tahirovic says. “Taken together, our findings not only shed new light on fundamental disease mechanisms, but may also have practical implications for NPC patients.”