Advanced Imaging Studies in Progressive Supranuclear Palsy

Lay Summary

Correlating Brain Changes with Disease Progression in Progressive Supranuclear Palsy Using MRI

This research aims to identify structural brain changes that occur over the course of progressive supranuclear palsy (PSP) and relate explicit brain changes to the onset of specific signs and symptoms of the disease.

PSP is a devastating neurodegenerative disease. It occurs in people after the age of 40. Patients initially develop severe problems with balance and fall easily. Then they lose facial expression, have difficulty moving their eyes, develop rigid muscles on both sides of the body, have difficulty moving, and in the late stages develop difficulties speaking and then swallowing. Death usually occurs within eight years after disease onset. While prior studies using MRI have shown that the entire brain shrinks, indicating brain cell loss, it is likely that certain brain structures shrink faster than others. Moreover, it is also likely that specific structural changes are directly linked to the onset or progression of distinct clinical features of the disease.

The investigators will use a new technique with MRI imaging, called tensor-based morphometry, to assess changes in the brain’s structures over the course of the disease in 24 PSP patients. Each patient will undergo clinical exams, followed by MRI imaging, five times over a two-year period. Through this technique, the investigators will map three-dimensional profiles of brain atrophy over time in specific areas of the brain in patients to determine which brain regions are changing and what the rates of change are over time.

Through this process, they will answer three questions: (1) Which regions of the brain change over time? (2) What is the trajectory of cell loss for each brain region? and (3) How do rates of brain atrophy correlate with changes in specific clinical signs and patients’ symptoms over the course of the illness?

They hypothesize that regional changes occur in the brain’s lateral frontal lobe, striatum and midbrain, and that the rate of atrophy in at least one of these areas slows rather than increases over time. Imaging, therefore, may differentiate atrophy in PSP from that occurring in other neurodegenerative diseases. They also hypothesize that: changes in patients’ executive function (decision-making) correlates with lateral frontal lobe atrophy; patients’ general motor decline correlates with striatal atrophy; and progression of patients’ eye movement problems correlate with midbrain cell loss.

Abstract

Advanced Imaging Studies in Progressive Supranuclear Palsy

Progressive supranuclear palsy (PSP) is a neurodegenerative disease characterized clinically by the presence of vertical supranuclear palsy, early falls, symmetric akinetic-rigidity and levodopa unresponsiveness. Patients with PSP have a progressive course and typically die within eight years of onset. Very little is known about changes in brain structures over the disease course in PSP or how changes in specific brain structures are related to onset of specific clinical features.

Magnetic resonance imaging (MRI) has been increasingly recognized as a useful technique to demonstrate global and regional changes in neurodegenerative diseases. We and others have used cross-sectional MRI techniques to demonstrate the presence of regional cerebral atrophy in PSP. Longitudinal studies assess changes over time within individuals and therefore reduce the problem of inter-individual variation in brain volume. Importantly, they also permit the assessment of disease progression over time.

The PI and colleagues have used established registration based MRI techniques to demonstrate increased rates of global brain atrophy and increased rates of ventricular expansion over time in patients with PSP compared to normal controls. However, it is likely that rates of atrophy will vary across different regions of the brain.

Aims: (1) to identify which regions of the brain are changing over time, in patients with PSP; (2) to determine the trajectory of loss for each region identified in aim 1 and hence ultimately generate a 3D map of trajectories for PSP; and (3) to correlate regional rates of atrophy with changes in clinical signs and symptoms over time.

In order to accomplish these aims, 24 patients will undergo a clinical evaluation and have a volumetric head MRI scan every six months for two years. A novel technique called tensor-based morphometry (TBM) is available at Mayo Clinic and will be used to assess changes in the brain over time. This technique is automated and can map fully 3D profiles of volumetric atrophy in individual patients and can therefore be used to demonstrate which brain regions are changing over time.

Furthermore, TBM can be used to quantify rates of atrophy for different brain regions of interest. These rates will then be used in a mixed linear effects model to determine the trajectory for each region of interest. Trajectories of regional volume loss will be correlated with changes in clinical features that have occurred over the duration of the grant.

The results from this study will provide important information about disease progression in PSP and will be crucial for future clinical trials assessing disease modifying treatments.