Dysfunction and inflammation of the blood-brain barrier associated with Down syndrome regression disorder

Dysfunction and inflammation of the blood-brain barrier associated with Down syndrome regression disorder

A new research study led by Jonathan D. Santoro, MD, director of the Neuroimmunology Program at Children's Hospital Los Angeles, shows evidence of blood-brain barrier dysfunction and central nervous system inflammation in individuals with Down syndrome regression disorder (DSRD).

The new study, “Evidence of blood-brain barrier dysfunction and CSF immunoglobulin synthesis in regression disorders of Down syndrome,” was published in theAnnals of clinical and translational neurologyOn February 25, 2025. It was written by Dr. Santoro led in collaboration with Saba Jafarpour, MD, Natalie K. Boyd, Benjamin N. Vogel, Lina Nguyen and Lilia Kazerooni from Chla's Neurological Institute. The team worked closely with the University of Colorado Linda Crnic Institute and its director Dr. Joaquin Espinosa together.

This is a big missing piece in the puzzle of what we know about Down syndrome regression disorder. “

Dr. Jonathan D. Santoro, MD, director of the Neuroimmunology Program, Children's Hospital Los Angeles

Leading DSRD research efforts

In recent years, Dr. Santoro, Dr. Jafarpour and her team led several research efforts in the Strategic Therapies for Overcoming Reactive Immunology (Storm) Laboratory and the development of new treatments for DSRD. This rare but increasingly diagnosed condition is leading to a rapid decline in young people with Down syndrome. High-functioning individuals abruptly lose the ability to communicate, feed themselves, sleep, dress themselves, or use the bathroom. Some people with the disorder become immobile and catatonic.

Although DSRD was first described in a paper in 1946, it has not been studied extensively as many assumed it was a psychiatric condition or a potentially early-onset Alzheimer's disease, all of which are well described in this population. But Dr. Santoro's team saw patients with DSRD and studied it further. Her early research identified inflammatory markers in patients' cerebrospinal fluid, indicating that DSRD may actually be an inflammatory condition that affects the brain. “This was the AHA moment,” says Dr. Santoro.

This discovery informed Dr. Santoro for DSRD and began administering high-dose steroids as well as immunotherapy known as intravenous immunoglobin (IVIG). This approach proved to be very effective and allowed patients to regain the ability to walk, run and communicate.

However, clinical investigations have identified abnormalities in the cerebrospinal fluid suggestive of neuroinflammation in only a fraction of patients with DSRD, which is inconsistent with the high success rate of immunotherapy among this population. The team of Dr. Santoro and her collaborators at the University of Colorado continued their detailed research.

New evidence of DSRD as an inflammatory disease

This latest study provides clear evidence that DSRD is indeed an inflammatory disease. It also links DSRD to dysfunction of the blood-brain barrier, a layer of cells that forms a membrane between the blood and the brain to filter out harmful substances. “The blood-brain barrier is crucial for keeping the immune system out of the brain,” explains Dr. Santoro. “Any disorder could be enough to cause neurological disease.”

The new study included cerebrospinal fluid samples from three different patient populations: people with DSRD, people with a known neuroimmunological or neuroinflammatory condition, such as multiple sclerosis or autoimmune encephalitis, and a neurotypical, non-inflammatory control group.

Proteome profiling of samples from these individuals allowed researchers to study the proteins they found. Metabolomic profiling identified the metabolites - the molecules produced when foods, drugs, chemicals or tissues are broken down, allowing researchers to identify the functional status of cells in the body. And immune marker profiling analyzed the specific molecules expressed by immune cells in the samples.

Indications for inflammation and dysfunction of the blood-brain barrier

The data showed increased dysregulation in samples from DSRD and neuroinflammatory patients compared to healthy control patient samples, particularly upregulation of several immunoglobulin sequences indicative of neuroinflammation. Furthermore, the DSRD patient samples showed significant upregulation of erythrocyte proteins and liver-derived plasma proteins, indicating poor blood-brain barrier integrity. The immune marker profile of the DSRD patient samples was also similar to various other neuroimmunological diseases.

Based on these results, Dr. Santoro and his team found that the cerebrospinal fluid of individuals with DSRD has proteomic and metabolic signatures consistent with both neuroinflammation and increased permeability of the blood-brain barrier.

“The proteomic abnormalities identified in this study confirm what we have seen in clinical practice – the immune system is an important player in DSRD,” says Dr. Santoro.

The cerebrospinal fluid of DSRD patients is also more comparable to that of patients with neuroinflammatory diseases than to healthy controls, suggesting a potential immune-related cause of DSRD that could influence future treatment strategies.

“The implications of these findings are profound and will hopefully serve as the next step in determining the cause of DSRD,” explains Dr. Santoro.

This research has led to a Phase IIB clinical trial evaluating the safety and effectiveness of immunotherapy in individuals with DSRD. This clinical trial, conducted with the University of Colorado Linda Crnic Institute, is the first of its kind in the treatment of DSRD.

Like Dr. Santoro says, “We’ve come a long way, but we have more work to do!”

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