An international study led by researchers from the Sant Pau Research Institute (IR Sant Pau) shows that advanced use of magnetic resonance imaging (MRI) allows much more accurate identification of patients with progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). These are two rare and clearly underdiagnosed atypical parkinsonian disorders.
The study, published in The Journal of Prevention of Alzheimer’s Disease, shows that this strategy improves early diagnosis and transforms the design of clinical trials, making them more precise and feasible for diseases for which no disease-modifying treatment currently exists.
“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, researcher in the Neurobiology of Dementias Group at IR Sant Pau and neurologist at Hospital de Sant Pau. He is the first author of the study. “This means they are greatly underdiagnosed, and for years we have not known with enough certainty which disease each patient actually had.”
What PSP and CBD Are and Why They Are Confused with Parkinson’s Disease
PSP and CBD belong to a group of neurodegenerative diseases known as tauopathies, which are characterized by the abnormal accumulation in the brain of tau protein, a protein essential for normal neuronal function.
When tau is deposited pathologically, it causes progressive damage to different brain regions. In PSP and CBD, this damage particularly affects areas involved in movement control, balance, posture, speech, and certain cognitive functions, which explains why their initial symptoms closely resemble those of Parkinson’s disease.
Unlike Alzheimer’s disease—another well-known tauopathy—PSP and CBD belong to the subgroup of four-repeat tauopathies, with their own distinct biological characteristics. However, for years these differences could not be clearly identified during life, leading to imprecise diagnoses and significant clinical confusion.
“These diseases are, in a way, halfway between Alzheimer’s and Parkinson’s,” notes Dr. Ignacio Illán-Gala, researcher in the Neurobiology of Dementias Group at IR Sant Pau and neurologist at Hospital de Sant Pau, and 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.”
Imprecise Diagnoses and Clinical Trials That Fail
For years, the lack of objective diagnostic tools has been one of the main obstacles to treatment development in these tauopathies. Patient selection for clinical trials has relied almost exclusively on clinical criteria, especially in early stages, when symptoms are still nonspecific and overlap across different diseases.
The same clinical syndrome can correspond to different underlying pathologies, and the same disease can manifest in very different ways. This heterogeneity has led many clinical trials to include biologically mixed populations, drastically reducing their ability to detect true therapeutic benefits.
This issue is particularly relevant in CBD, where a significant proportion of patients in fact have Alzheimer’s disease. Without adequate biological filtering, the cohorts used in clinical trials are biologically contaminated, critically limiting their usefulness.
How Magnetic Resonance Imaging Makes It Possible to Differentiate PSP and CBD
The study indicates that structural magnetic resonance imaging can address 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 patterns of brain atrophy in detail, the researchers developed models capable of estimating with high probability whether a patient has PSP or CBD, even at very early stages of the disease. “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.”
The key to the study lies in identifying disease-specific MRI signatures based on the combination of structural changes across different brain regions. In PSP, the signature is characterized mainly by involvement of deep brain structures, particularly the brainstem, together with more selective changes in certain cortical areas. In CBD, the pattern is different and shows more marked involvement of cortical regions, especially those related to motor control and sensory integration.
“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.”
Smaller, Feasible Clinical Trials with Real Impact for Patients
Beyond improving diagnostic accuracy, the study proves that MRI can also 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, the researchers demonstrate that it is possible to detect structural brain changes with much greater sensitivity than with traditional clinical scales.
In classic trial designs based on clinical variables—such as functional or symptom severity scales—demonstrating that a treatment modifies disease progression usually requires long follow-up periods and considerable sample sizes, often reaching several hundred patients. This approach is especially problematic in rare diseases such as PSP and CBD, where recruitment is slow, costly, and difficult to sustain over time.
Analyses performed in the study show that using MRI as an outcome measure substantially changes this scenario. In PSP, applying disease-specific MRI signatures could reduce the number of participants required by approximately 50% in a 12-month clinical trial compared with designs based solely on clinical scales. In CBD, where clinical and diagnostic heterogeneity is even greater, the impact is even more pronounced: use of these objective measures could lead to an approximately 80–85% reduction in the required sample size to detect a therapeutic effect with the same statistical power.
“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.”
In this context, the researchers emphasize that these are not merely rare diseases but conditions that are both infrequent and clearly underdiagnosed. Methodological limitations have so far been a key barrier to therapeutic development and to the availability of real options for patients.
Research Continuity and New PERIS-Funded Lines of Work
This line of research has direct continuity in projects currently underway at IR Sant Pau. In the 2025 call of the PERIS program of the Department of Health of the Government of Catalonia, the center received funding to advance the early diagnosis of four-repeat tauopathies, including PSP and CBD. This is done through the combination of plasma biomarkers and advanced imaging techniques.
This project, led by Dr. Illán-Gala, builds directly on the results now published and aims to shift diagnosis toward minimally symptomatic stages, when future disease-modifying 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.”
END