Proteomic signatures in cerebrospinal fluid and their clinical associations in patients with ME/CFS

Why this study matters

For people living with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), the illness can feel invisible: crippling fatigue, pain, and brain fog, yet normal results on many routine medical tests. This study looks directly at the clear fluid that bathes the brain and spinal cord, searching its protein content for clues that might explain symptoms, disease severity, and links to problems with standing and heart rate. It offers a window into how the brain and immune system may be involved in this complex condition.

Looking into the brain’s surrounding fluid

Instead of focusing on blood tests, the researchers examined cerebrospinal fluid, which closely reflects what happens in and around the brain. They collected samples from 31 adults with ME/CFS, most of whom reported poor quality of life and substantial pain and fatigue. Using high-resolution mass spectrometry, a tool that can detect hundreds of proteins at once, they measured levels of 902 different proteins in the fluid. They then compared these protein patterns with clinical features such as overall illness severity and the presence of postural orthostatic tachycardia syndrome (POTS), a condition where heart rate jumps abnormally when standing.

Links between heart rate problems and inflammation

One question was whether people with both ME/CFS and POTS show different protein patterns than those without POTS. While no single protein cleared the strictest statistical bar, groups of proteins pointed to shared biological themes. People with POTS showed signs of heightened activity in white blood cells called neutrophils and in platelets, which help blood clot. These patterns suggest ongoing low-grade inflammation and possible changes in small blood vessels affecting the brain and nervous system. Such changes could contribute to lightheadedness, rapid pulse, and other symptoms when standing.

Patterns that track with how sick people feel

The team also grouped participants by clinical severity: mild, moderate, or severe ME/CFS. They found sets of proteins that differed between these groups, with the most striking changes in those who were most disabled. Pathway analysis showed stronger signals from the body’s complement system, which is part of immune defense, and from clotting-related proteins in the most severe cases. These findings fit with emerging ideas about “thrombo-inflammation,” where immune and clotting systems interact, potentially affecting blood flow and nerve function. They also saw changes in proteins involved in transporting insulin-like growth factors, hinting at altered energy or growth-related signaling in severe illness.

Protein ratios as potential illness gauges

Rather than looking only at individual proteins, the researchers calculated ratios between pairs of proteins, reasoning that relative levels might better capture ongoing processes. One ratio, between proteins called YWHAG and NPTX2, rose with ME/CFS severity and has previously been tied to cognitive decline in Alzheimer’s disease, suggesting a shared pattern of stress on nerve connections. Three other protein pairs stood out as tracking closely with how sick participants were. Together, these ratios point toward increased cellular stress, remodeling of the material surrounding cells, and a tight interplay between immune activity and nerve signaling in ME/CFS.

What this means for people with ME/CFS

This work does not yet deliver a ready-made diagnostic test, and the authors emphasize that their findings are exploratory and based on a relatively small group without healthy controls. Still, the results strengthen the case that ME/CFS involves real, measurable changes in the brain’s surrounding fluid, especially in immune, clotting, and nerve-related pathways. If confirmed in larger studies, specific protein patterns and ratios in cerebrospinal fluid could help explain why some people are more severely affected than others and guide the search for objective markers and future treatments.

Citation: Bragée, B., Li, P., Meadows, D. et al. Proteomic signatures in cerebrospinal fluid and their clinical associations in patients with ME/CFS. Sci Rep 16, 15848 (2026). https://doi.org/10.1038/s41598-026-46965-1

Keywords: ME/CFS, cerebrospinal fluid, proteomics, POTS, disease severity