Advanced Imaging Studies in Progressive Supranuclear Palsy
Keith Josephs, MST, M.D.
Mayo Clinic, Rochester, MN, Divisions of Behavioral Neurology & Movement Disorders
David Mahoney Neuroimaging Program
June 2009, for 3 years
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.
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.
Keith Josephs, MST, M.D.
Dr. Keith A. Josephs is an associate professor and consultant of neurology at the Mayo Clinic in Rochester, Minnesota. He received his bachelors and masters of science degrees in mathematics from the University of Florida. He completed his medical degree at the Medical College of Pennsylvania in Philadelphia, Pennsylvania, followed by a one-year internship and three-year neurology residency at the Mayo Clinic.
Following his residency he completed a fellowship in movement disorders at the Mayo Clinic. He then received the prestigious Mayo Foundation Scholarship to the United Kingdom where he completed a second fellowship in degenerative neuropathology and behavioral neurology.
His research focuses on clinical, imaging and pathological correlates of neurodegenerative disorders, in particular progressive supranuclear palsy. He has been a staff Neurologist at the Mayo Clinic since 2003. Since being on staff he has authored or co-authored over 130 peer reviewed publications and has received a KL2 grant from the National Institute of Health. He has received numerous scientific awards, including the 2009 Judson Daland Prize for Clinical Research from the American Philosophical Foundation.
Josephs KA, Whitwell JL, Eggers SD, Senjem ML, Jack CR. Grey matter correlates of behavioral severity in progressive supranuclear palsy. Movement Disorders 2011; 26: 493-8
Whitwell JL, Master AV, Avula R, Kantarci K, Eggers SD, Edmonson HA, Jack CR, Josephs KA. Clinical correlates of white matter tract degeneration in PSP. Archives of Neurology 2011;68: 753-760
Whitwell JL, Avula R, Master A, Vemuri P, Senjem ML, Jones DT, Jack CR, Josephs KA. Disrupted thalamocortical connectivity in PSP: A resting state fMRI, DTI, VBM study.Parkinsonism & Related Disorders 2011;17(8):599-605.
Whitwell JL, Xu J, Mandrekar JN, Gunter JL, Jack CR, Josephs KA. Rates of brain atrophy and clinical decline over 6 and 12 month intervals in PSP: determining sample size for treatment trials. Parkinsonism and Related Disorders 2001 [Nov 11 Epub] We also have a further two manuscripts in submission:
Whitwell JL, Xu J, Mandrekar J, Gunter JL, Jack CR, Josephs KA. Imaging measures predict change over time in the progressive supranuclear palsy rating scale. Submitted to Movement Disorders.
Josephs KA, Eggers SD, Jack CR, Whitwell JL. Neuroanatomical correlations of the progressive supranuclear palsy and corticobasal syndrome hybrid. Submitted to European Journal of Neurology.
1) Whitwell JL, Avula R, Master A, Vemuri P, Senjem ML, Jones DT, Jack CR, Josephs KA. Dusrupted functional connectivity along the dentatorubrothalamic to cortex pathways in PSP: A resting state fMRI, DTI and VBM study. Neurology 2011; 76 (Suppl 4): 639
Whitwell JL, Avula R, Master A, Vemuri P, Senjem ML, Jones DT, Jack CR, Josephs KA. The relationship between disrupted functional connectivity and structural damage in PSP: a resting state fMRI, DTI, VBM study. Movement Disorders 2011; 26 (Suppl 2): S255
Josephs KA, Gunter JL, Jack CR, Whitwell JL. Changes in clinical and imaging measures can be detected over a short interval of only 6 months in subjects with progressive supranuclear palsy. Movement Disorders 2011; 26 (Suppl 2): S338.
Avula R., Edmonson H.A., Eggers S.D., Jack Jr. C.R., Josephs K.A., Kantarci K., Master A.V., Whitwell J.L. (2011) Clinical Correlates of White Matter Tract Degeneration in Progressive Supranuclear Palsy.
Eggers S.D., Jack Jr. C.R., Josephs K.A., Senjem M.L., Whitwell J.L. Gray Matter Correlates of Behavioral Severity in Progressive Supranuclear Palsy. (2011)
Eggers S. D., Jack Jr. C. R. Josephs K. A., and Whitwell J. L. Neuroanatomical correlates of the progressive supranuclear palsy corticobasal syndrome hybrid. (2012)
Gunter J.L., Jack Jr. C.R., Josephs K.A., Mandrekar J., Whitwell J.L., Xu J. Imaging Measures Predict Progression in Progressive Supranuclear Palsy. (2012)
Coon E.A., Jack Jr. C.R., Josephs K.A., Whitwell J.L. Primary Lateral Sclerosis as Progressive Supranuclear Palsy: Diagnosis by Diffusion Tensor Imaging. (2012)
Gunter J.L., Jack Jr. C.R., Josephs K.A., Mandrekar J., Whitwell J.L., Xu J. Rates of brain atrophy and clinical decline over 6 and 12-month intervals in PSP: Determining sample size for treatment trials. (2012)
Avula R., Jack Jr. C.R., Jones D.T., Josephs K.A., Mastera A., Senjem M.L., Vemuria R., Whitwell J.L.
Disrupted thalamocortical connectivity in PSP: A resting-state fMRI, DTI, and VBM study. (2011)