Radiological biomarkers for diagnosis in PSP: Where are we and where do we need to be?

Abstract

PSP is a pathologically defined neurodegenerative tauopathy with a variety of clinical presentations including typical Richardson's syndrome and other variant PSP syndromes. A large body of neuroimaging research has been conducted over the past two decades, with many studies proposing different structural MRI and molecular PET/SPECT biomarkers for PSP. These include measures of brainstem, cortical and striatal atrophy, diffusion weighted and diffusion tensor imaging abnormalities, [18F] fluorodeoxyglucose PET hypometabolism, reductions in striatal dopamine imaging and, most recently, PET imaging with ligands that bind to tau. Our aim was to critically evaluate the degree to which structural and molecular neuroimaging metrics fulfill criteria for diagnostic biomarkers of PSP. We queried the PubMed, Cochrane, Medline, and PSYCInfo databases for original research articles published in English over the past 20 years using postmortem diagnosis or the NINDS-SPSP criteria as the diagnostic standard from 1996 to 2016. We define a five-level theoretical construct for the utility of neuroimaging biomarkers in PSP, with level 1 representing group-level findings, level 2 representing biomarkers with demonstrable individual-level diagnostic utility, level 3 representing biomarkers for early disease, level 4 representing surrogate biomarkers of PSP pathology, and level 5 representing definitive PSP biomarkers of PSP pathology. We discuss the degree to which each of the currently available biomarkers fit into this theoretical construct, consider the role of biomarkers in the diagnosis of Richardson's syndrome, variant PSP syndromes and autopsy confirmed PSP, and emphasize current shortfalls in the field. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Keywords: diagnosis; magnetic resonance imaging; positron emission tomography; progressive supranuclear palsy; single-photon emission computed tomography.

Figure 1. Structural MRI demonstrating the morphological characteristics of PSP-RS and brainstem measurements

Top left sagittal slice shows the hummingbird sign with atrophy of the dorsal midbrain and relative preservation of the pons. Top right axial slice through the midbrain shows rounded midbrain peduncles (Mickey Mouse sign) and concavity of the lateral margin of the midbrain tegmentum (Morning glory sign, arrow). Bottom images show example measurements of the midbrain anteroposterior (AP) diameter, midbrain and pons area, superior cerebellar peduncle width and middle cerebellar peduncle width (modified from).

Figure 2. FDG-PET, DAT and tau PET findings in PSP-RS

Panel A shows a statistical stereotactic surface projection map of an FDG-PET scan for a PSP-RS patient where Z score values represent differences from a normal cohort and are color coded as indicated in the color scale (0 = normal; 7 = most abnormal). Hypometabolism is observed in the frontal lobes, midbrain and caudate nucleus. Panel B demonstrates absent putamen DAT binding and reduced caudate binding in a patient with PSP-RS compared to a control subject. Panels C and E show [¹⁸F]AV-1451 results. Panel C shows [¹⁸F]AV-1451 tau-PET scans in a patient with PSP-RS and an age-matched control. The control shows some uptake in midbrain and basal ganglia, although uptake in these regions is greater in the PSP-RS patient. In addition, the PSP-RS patient shows uptake in the dentate nucleus of the cerebellum and thalamus. Panel E shows group-level [¹⁸F]AV-1451 findings in 10 patients with PSP-RS compared to healthy controls. Increased uptake in PSP-RS compared to controls is identified in dentate nucleus of the cerebellum, midbrain, thalamus, and basal ganglia (Modified from). Panels D and F show THK-5351 results. Panel D shows a THK-5351 tau-PET scan in a patient with PSP-RS and a healthy control. The control and PSP-RS patient show uptake in the midbrain, thalamus, and basal ganglia, although the degree of uptake is greater in PSP-RS. Panel F shows group-level THK-5351 findings in 10 patients with PSP-RS compared to healthy controls. Increased uptake in PSP-RS compared to controls is identified in midbrain, thalamus, basal ganglia and posterior lateral and medial frontal lobe. Modified from.