An international study led by researchers from the Sant Pau Research Institute (IR Sant Pau) has revealed that advanced magnetic resonance imaging (MRI) techniques significantly enhance the identification of patients with progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). These findings, published in The Journal of Prevention of Alzheimer’s Disease, promise to improve early diagnosis and refine clinical trial designs for these underdiagnosed atypical parkinsonian disorders.
“These are diseases that cause balance problems, falls, stiffness, or difficulties with speech and movement. Many patients initially present as if they had Parkinson’s disease or are simply older adults with mobility difficulties,” explains Dr. Jesús García-Castro, a researcher in the Neurobiology of Dementias Group at IR Sant Pau and neurologist at Hospital de Sant Pau. He is the study’s first author. “This means they are greatly underdiagnosed, and for years we have not known with enough certainty which disease each patient actually had.”
Understanding PSP and CBD: Misdiagnosed and Misunderstood
PSP and CBD are part of a group of neurodegenerative diseases known as tauopathies, characterized by the abnormal accumulation of tau protein in the brain, essential for normal neuronal function. When tau is deposited pathologically, it causes progressive damage to brain regions involved in movement control, balance, posture, speech, and certain cognitive functions, leading to symptoms resembling Parkinson’s disease.
Unlike Alzheimer’s disease—another tauopathy—PSP and CBD are classified as four-repeat tauopathies, with distinct biological characteristics. However, these differences have historically been difficult to identify, resulting in imprecise diagnoses and significant clinical confusion.
“These diseases are, in a way, halfway between Alzheimer’s and Parkinson’s,” notes Dr. Ignacio Illán-Gala, senior author of the study. “They resemble Parkinson’s because of their motor symptoms, but they share with Alzheimer’s the fact that they are caused by tau pathology. The problem is that, until now, we did not have reliable tools to distinguish them properly.”
Challenges in Diagnosis and Clinical Trials
For years, the absence of objective diagnostic tools has hindered treatment development for these tauopathies. Clinical trials have relied almost exclusively on clinical criteria, especially in early stages, when symptoms are nonspecific and overlap across different diseases. This has led to trials with biologically mixed populations, reducing their ability to detect true therapeutic benefits.
The issue is particularly pronounced in CBD, where many patients may actually have Alzheimer’s disease. Without adequate biological filtering, clinical trial cohorts become biologically contaminated, critically limiting their usefulness.
The Role of MRI in Differentiating PSP and CBD
The study highlights how structural MRI can fill a long-standing gap in these tauopathies: the absence of reliable in vivo biomarkers capable of identifying the true underlying pathology when symptoms are still nonspecific. By analyzing brain atrophy patterns, researchers developed models capable of estimating with high probability whether a patient has PSP or CBD, even at early stages.
“MRI has two fundamental functions,” explains Dr. García-Castro. “On the one hand, it helps us diagnose much more reliably at early stages. On the other hand, it allows us to measure disease progression objectively.”
“Although they may look very similar clinically, at the brain level PSP and CBD damage the brain in different ways,” says Dr. Illán-Gala. “These differences are reflected on MRI, and by combining them into a signature, we can much better determine which disease each patient has.”
Implications for Clinical Trials and Patient Outcomes
Beyond improving diagnostic accuracy, the study demonstrates that MRI can be used as a longitudinal follow-up tool in clinical trials targeting these tauopathies. By using disease-specific MRI signatures as objective measures of disease progression, researchers showed it is possible to detect structural brain changes with greater sensitivity than traditional clinical scales.
In classic trial designs based on clinical variables, demonstrating treatment efficacy requires long follow-up periods and large sample sizes, often reaching several hundred patients. This is problematic in rare diseases like PSP and CBD, where recruitment is slow and costly.
Analyses indicate that using MRI as an outcome measure could reduce the number of participants required by approximately 50% in a 12-month clinical trial for PSP. In CBD, this reduction could be as high as 80–85%.
“For a company or an academic consortium to commit to a clinical trial, it has to be feasible,” adds Dr. Illán-Gala. “If a trial requires a thousand patients, it is practically impossible. But if it can be conducted with a reasonable number of well-selected individuals and objective measures of progression, then there is a real chance of demonstrating whether a treatment works.”
Future Directions and Research Continuity
This research has direct continuity in projects currently underway at IR Sant Pau. The center has received funding from the PERIS program of the Department of Health of the Government of Catalonia to advance early diagnosis of four-repeat tauopathies, including PSP and CBD, through plasma biomarkers and advanced imaging techniques.
This project, led by Dr. Illán-Gala, builds on the published results and aims to shift diagnosis toward minimally symptomatic stages, when future treatments are more likely to be effective. “Our goal is to reach a situation similar to that of Alzheimer’s disease, where a combination of a blood test and an MRI scan allows these diseases to be diagnosed at very early stages and with much greater confidence,” explains Dr. García-Castro.
“These conditions are far more common than we think, but we do not know how to detect them properly,” concludes Dr. García-Castro. “Improving diagnosis is the first step so that these patients, who currently have no therapeutic options, can begin to have them.”
