Protein cues can unlock early diagnosis of “middle-aged dementia”

Scientists have identified unique protein patterns in spinal fluids in patients with frontotemporal dementia (FTD), which has the potential to open the door to early diagnosis for this devastating middle-aged brain disease and have better treatment options.

Researchers at the University of California, San Francisco (UCSF) analyzed more than 4,000 cerebrospinal fluid proteins, revealing molecular characteristics that can alter this frequently diagnosed state.

The discovery published today in Natural Aging offers hope for addressing a disease that usually hits adults in the 1940s and 1960s and is often confused with psychiatric disorders such as depression or schizophrenia. What makes this finding particularly valuable is that it has the potential to identify the situation earlier when the intervention is likely to be most effective.

But what exactly happens to the brains of people with FTD, and how will these protein patterns lead to diagnostic breakthroughs?

Discover molecular fingerprints of FTD

UCSF researchers led by Dr. Rowan Saloner examined spinal fluid from 116 genetic forms of FTD and 39 non-vector family members. By focusing on individuals with genetic forms of disease, the team can study confirmed cases of disease in living patients – previously impossible for most FTD cases, only to be clearly diagnosed after death.

“FTD affects people in life and deprives them of independence,” professor at the UCSF Center for Memory and Aging and the corresponding author of the paper. “But unlike other dementias, such as Alzheimer’s, there is no clear way to diagnose it in a living patient.”

The team found that several protein networks in patients with FTD continued to change. These patterns are divided into four main categories:

• RNA processing problems (especially in vectors with C9ORF72 and GRN mutations)
• Extracellular matrix changes (especially in MAPT mutation vectors)
• Synaptic/neuron protein reduction
• Reduce autophagy modular proteins (involved in cell cleaning processes)

Scientists are particularly interested in the changes that occur before symptoms develop. They identified reduced levels of proteins responsible for ion transport in C9ORF72 and MAPT mutations, suggesting that changes in neural signaling may occur before extensive brain degeneration.

Verification across different FTD types

A key aspect of the study is to determine whether these protein characteristics appear only in the genetic form of FTD or represent a broader disease mechanism. The researchers tested their findings in independent groups of different FTD types.

When they examined patients with progressive supranuclear paralysis (PSP) in the occasional form of FTD tauopathy, they found many of the same protein patterns. This suggests that the identified signature may be relevant on various forms of FTD, not just inherited cases.

The team also tested whether these protein changes could distinguish FTD from other neurodegenerative diseases such as Alzheimer’s disease. Several protein modules effectively differentiate FTD with healthy controls and Alzheimer’s patients, thereby enhancing its potential diagnostic value.

From laboratory discovery to clinical use

Newly identified protein characteristics can alter the development of FTD diagnosis and treatment in a variety of ways:

In networks associated with cognitive decline, neuronal pentapeptides (NPTX2 and NPTX1) become particularly important “hub proteins”. NPTX2 showed the strongest association with cognitive deterioration among all the proteins examined, making it a promising biomarker candidate.

The study also reveals a unique pattern of proteins associated with RNA processing, whereas RNA-processed proteins are elevated in FTD but not in Alzheimer’s disease or Parkinson’s disease, which may provide markers of specific diseases.

“If we can identify FTD as early as possible, maybe using some of the proteins we identified, we can direct patients to the right resources to get them into the right treatment trials and ultimately hope, we hope, provide them with precise treatment,” Saloner noted.

The future of FTD research and treatment

This study represents the highest number of proteins measured in FTD spinal fluid to date. These findings not only improve our understanding of the mechanisms of the disease, but also highlight the promising goals of future diagnostic testing and therapies.

The patients were from the Allftd Alliance and were led by UCSF study co-authors Adam Boxer, MD, Adam Boxer, MD, Howie Rosen, MD, and Brad Boeve, MD, Mayo Clinic. Dr. Kaitlin Casaletto, professor at the UCSF Center for Memory and Aging, has served as senior author.

For an estimated 50,000-60,000 Americans living in FTD, these findings offer new hope. The possibility of reliable biological markers can greatly reduce the current average diagnosis time of 3.6 years, allowing earlier intervention and better disease management.

As the study continues to targeted therapy for FTD, the protein characteristics identified in this study can not only help identify patients early, but also monitor treatment effects in clinical trials. With the development of several potential FTD therapies, it is becoming increasingly important to have reliable markers for tracking disease progression.