Progressive supranuclear palsy: Advances in diagnosis and management

Abstract

Progressive supranuclear palsy (PSP) is a complex clinicopathologic disease with no current cure or disease modulating therapies that can only be definitively confirmed at autopsy. Growing understanding of the phenotypic diversity of PSP has led to expanded clinical criteria and new insights into etiopathogenesis that coupled with improved in vivo biomarkers makes increased access to current clinical trials possible. Current standard-of-care treatment of PSP is multidisciplinary, supportive and symptomatic, and several trials of potentially disease modulating agents have already been completed with disappointing results. Current ongoing clinical trials target the abnormal aggregation of tau through a variety of mechanisms including immunotherapy and gene therapy offer a more direct method of treatment. Here we review PSP clinicopathologic correlations, in vivo biomarkers including MRI, PET, and CSF biomarkers. We additionally review current pharmacologic and non-pharmacologic methods of treatment, prior and ongoing clinical trials in PSP. Newly expanded clinical criteria and improved specific biomarkers will aid in identifying patients with PSP earlier and more accurately and expand access to these potentially beneficial clinical trials.

Keywords: Gene therapy; Immunotherapy; Progressive supranuclear palsy; Tauopathy; Treatment.

Figure 1:. Clinicopathologic Complexity of PSP.

PSP neuropathology may be associated with a number of different clinical phenotypes (shown in light blue boxes with rounded edges). Other neuropathologies that may also present with these clinical phenotypes are shown in the lower row. Green: Tau, Orange: alpha-synuclein, Yellow: Alzheimer’s disease, Purple: TDP-43. Abbreviations: PAGF: pure akinesia freezing of gait, CBS: corticobasal syndrome, bvFTD: behavioral variant FTD, PPA: primary progressive aphasia, PLS: primary lateral sclerosis, PD/DLB: Parkinson’s Disease/dementia with Lewy bodies, MSA: multiple systems atrophy, CBD: corticobasal degeneration, PSP: progressive supranuclear palsy, AD: Alzheimer’s disease, TDP-43: TAR DNA binding protein 43.

Figure 2:. Pathologic Distribution and Clinical Correlations in PSP

A. Common clinical features of PSP associated with pathology in these affected regions. B. Regions in red commonly affected by PSP tau pathology and gliosis including, frontal, temporal, parietal lobes, globus pallidus, putamen, caudate, subthalamic nucleus, hippocampus, midbrain tectum and tegmentum, substantia nigra, pontine base and locus ceruleus, inferior olivary nucleus. Darker areas or red are more commonly affected. Certain phenotypes are more likely to exhibit pathology in specific areas (i.e. PSP-SL and temporal lobe pathology and PSP-CBS with parietal lobe pathology) C. Characteristic microscopic lesions seen in PSP after immunohistochemical staining for phospho-tau with AT8 antibody. Upper row shows two tufted astrocytes, bottom left showing coiled bodies (asterisk), bottom right showing globose neurofibrillary tangles. Scale bar is 50 μm.