Rates of brain atrophy and clinical decline over 6 and 12-month intervals in PSP: Determining sample size for treatment trials
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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2020, Parkinsonism and Related DisordersCitation Excerpt :Previous studies [5–7] have identified global and regional MRI changes in PSP over the course of 6 months or longer. Some authors [5,6] reported in PSP patients rates of midbrain atrophy over 6 months which was further reduced over 12 months, and others found a significant 1-year change in the volume of third ventricle, midbrain and frontal lobe [7]. In the recent years, Magnetic Resonance Parkinsonism Index (MRPI = midsagittal area of the pons/midbrain ratio multiplied by the middle cerebellar peduncle width/superior cerebellar peduncle width ratio [8]) has been shown to be a highly accurate measure in discriminating patient affected by PSP from patients affected by Parkinson's disease (PD) or other parkinsonisms [8–12].
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2017, Psychiatry Research - NeuroimagingCitation Excerpt :Furthermore, a number of notable multimodal studies have attempted to better define the pattern of thalamic atrophy in PSP: using diffusion tensor imaging (DTI) and structural MRI (VBM study), thalamic atrophy has been reported to involve the pulvinar, mediodorsal thalamic nucleus and anterior thalamic nucleus bilaterally (Padovani et al., 2006); and using resting state functional MRI (fMRI), DTI and structural MRI, reduced thalamic functional connectivity was reported, with DTI data implicating the ventral lateral (or motor) thalamus (Whitwell et al., 2011). In addition, longitudinal MRI studies using automated segmentation techniques show that the thalamus undergoes progressive atrophy over time in PSP (Whitwell et al., 2012). Few if any studies have utilized manual segmentation techniques and morphological analysis of the thalamus in patients with PSP.