Rates of brain atrophy and clinical decline over 6 and 12-month intervals in PSP: Determining sample size for treatment trials

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Abstract

Imaging biomarkers are useful outcome measures in treatment trials. We compared sample size estimates for future treatment trials performed over 6 or 12-months in progressive supranuclear palsy using both imaging and clinical measures. We recruited 16 probable progressive supranuclear palsy patients that underwent baseline, 6 and 12-month brain scans, and 16 age-matched controls with serial scans. Disease severity was measured at each time-point using the progressive supranuclear palsy rating scale. Rates of ventricular expansion and rates of atrophy of the whole brain, superior frontal lobe, thalamus, caudate and midbrain were calculated. Rates of atrophy and clinical decline were used to calculate sample sizes required to power placebo-controlled treatment trials over 6 and 12-months. Rates of whole brain, thalamus and midbrain atrophy, and ventricular expansion, were increased over 6 and 12-months in progressive supranuclear palsy compared to controls. The progressive supranuclear palsy rating scale increased by 9 points over 6-months, and 18 points over 12-months. The smallest sample size estimates for treatment trials over 6-months were achieved using rate of midbrain atrophy, followed by rate of whole brain atrophy and ventricular expansion. Sample size estimates were further reduced over 12-month intervals. Sample size estimates for the progressive supranuclear palsy rating scale were worse than imaging measures over 6-months, but comparable over 12-months. Atrophy and clinical decline can be detected over 6-months in progressive supranuclear palsy. Sample size estimates suggest that treatment trials could be performed over this interval, with rate of midbrain atrophy providing the best outcome measure.

Introduction

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by vertical supranuclear gaze palsy, axial rigidity, and postural instability that leads to falls early in the disease course [1]. Imaging studies demonstrate that PSP is associated with atrophy of the brain, particularly the midbrain, premotor cortex, basal ganglia and thalamus [2], [3], [4], [5]. Although specific pathological diagnoses underlying PSP can vary, the vast majority have deposition of the abnormal protein tau, and hence PSP is classified as a tauopathy [6]. In the absence of a biomarker specific for tau, clinically diagnosed PSP is perhaps the best available construct to test therapies aimed at targeting tau. Indeed, clinical trials are already underway in PSP assessing treatments for tau. It is therefore critically important to identify disease biomarkers that can serve as outcome measures in these treatment trials.

Rates of brain atrophy measured over serial MRI have the potential to be one such biomarker. Rates of whole brain atrophy and ventricular expansion are increased in PSP compared to controls [7], [8], and rates of atrophy of regional structures, such as the midbrain and frontal lobe, are also increased in PSP [9]. Rates of brain atrophy correlate with clinical dysfunction and may hence be useful biomarkers of disease progression in PSP [9].

In this study, we aimed to determine whether rates of whole brain and regional atrophy could be useful outcome measures for treatment trials in PSP. We were particularly interested in determining whether sample size estimates would be reasonable for treatment trials performed over a short interval of only 6-months, compared to the more typical interval of 12-months. Shorter clinical treatment trials would serve to reduce patient burden, which could be particularly important for patients that progress rapidly [10], and would significantly shorten the time taken to develop successful treatments. In addition, we aimed to determine how sample size estimates for these imaging outcome measures compare to those calculated using a clinical rating scale developed to assess disease severity in PSP; the PSP rating scale (PSPRS) [11]. The PSPRS assesses all important signs and symptoms associated with PSP, including behavioral change, ocular-motor deficits, gait, and balance impairment.

Section snippets

Subjects

Between August 1st 2009 and July 8th 2010, we prospectively recruited all consecutive PSP subjects that were referred to the Department of Neurology at the Mayo Clinic, Rochester, Minnesota. All subjects were evaluated by a neurodegenerative specialist and PSP expert (KAJ), received a clinical diagnosis of PSP, and underwent standardized testing that included a volumetric MRI. Patients were followed longitudinally and received follow-up MRI and clinical assessments at 6 and 12-month intervals.

Results

At baseline, PSP showed significantly reduced volume of the thalamus and area of the midbrain, and increased volume of the ventricles, compared to controls (Table 1). No differences were observed across PSP and controls in volumes of the whole brain, superior frontal lobe or caudate nucleus.

The PSP patients showed significantly reduced volumes of the whole brain and thalamus, and area of the midbrain, and increased volume of the ventricles, at both 6 and 12-months compared to the baseline

Discussion

We have shown excellent sample size estimates based on data collected over only 6-months in a cohort of probable PSP patients, suggesting that short interval clinical treatment trials are a realistic possibility in PSP. Rate of midbrain atrophy appears to be the most useful outcome measure.

Increased rates of whole brain, midbrain, and thalamic atrophy, and ventricular expansion, were detected over 6-months in our cohort of probable PSP patients. No previous studies have assessed 6-month

Acknowledgments

This work was supported by the Dana Foundation; National Institutes of Health (grant numbers R01-DC010367, R01-AG037491, R21-AG38736, and R01-AG11378) and the Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Foundation. We would like to acknowledge Drs. Scott Eggers, J. Eric Ahlskog and Joseph Matsumoto for referring patients for this study.

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