Progressive supranuclear palsy: Advances in diagnosis and management
Introduction
The clinicopathological syndrome of Progressive supranuclear palsy (PSP) was originally described in 1964 by Drs. Steele, Richardson, and Olszewski where they detailed a series of patients with postural instability, ocular motor abnormalities, facial and cervical dystonia, dementia, and other features [1]. This seminal work also detailed the initial neuropathologic findings including argyrophyllic globose and flame-shaped inclusions in both the gray and white matter throughout brainstem, subcortical and neocortical regions and accompanying neuronal loss and white matter degeneration. Further study using immunohistochemistry ultimately revealed that these inclusions were accumulations of the tau protein affecting neurons, astrocytes, and glia in a variety of morphologies [2]. Tau is a microtubule associated protein which contributes to the stability of the axonal cytoskeleton. Due to alternative splicing of the of microtubule binding site domains E2, E3, and E10, six tau isoforms exist, either with 4 repeated domains (4R, which includes the E10 region), or 3 repeated domains (3R, which excludes E10) [3]. In Alzheimer's disease, tau pathology exists in a fairly even 3R/4R mix in paired helical filament conformation [[4], [5], [6]] which occurs in combination with amyloid-β plaque deposits. In contrast, PSP is a ‘pure tauopathy’, where tau accumulations composed primarily of 4R tau species are the pathogenic lesions. For this reason, PSP is often targeted for trials for anti-tau therapeutics. PSP and corticobasal degeneration (CBD), are both 4R tauopathies where tau species are arranged in straight filament conformations [7,8]. The differences in conformations are due to differing orientations of the C-shaped tau subunits that compose them, with 3R/4R tau subunits being directed towards each other resulting in the helical conformation, whereas in 4R tauopathies, the C-shaped subunits are positioned back to back [9]. While PSP and CBD are both 4R tauopathies, the pathological features of PSP are typically tufted astrocytes and globose neurofibrillary tangles, whereas CBD has astrocytic plaques and ballooned pale neurons with thready neuronal tau inclusions that affect cortical regions more severely than subcortical regions and in a distinct conformation from what is seen in PSP [10,11].
The prevalence of the classic Richardson syndrome presentation of PSP is approximately 6/100,000, with average age of onset in the mid-60s and disease duration of approximately 6 years [[12], [13], [14], [15]]. However, it has become increasingly recognized that multiple clinical phenotypes aside from the originally described Richardson syndrome phenotype may result from PSP pathology. PSP pathology may be found in patients with parkinsonism mimicking Parkinson's disease (PSP-P), frontotemporal dementia (PSP-F), and corticobasal syndrome (PSP-CBS), and others [[16], [17], [18]]. The growing recognition of the clinical spectrum of PSP pathology has resulted in an expanded research criteria for the diagnosis of PSP which incorporates these clinical phenotypes [19]. Consequently, more recent age-adjusted prevalence estimates in Europe have increased to 8.8–10.8/100,000 patients [13,20], and in Yonogo Japan, PSP age-adjusted prevalence increased from 5.8/100,000 patients in 1999 to 17/100,000 patients in 2010 [21,22]. This recognition has also increased the need for specific biomarkers to diagnose patients early during life; advancements have progressed in MRI, PET, and biofluid biomarkers in PSP. Despite these advances, current therapies for PSP remain symptomatic and disease-modulating medications remain elusive despite extensive efforts. Current strategies are focused on targeting the tau protein by different mechanisms including immunotherapy and gene therapy. Here, we review the clinicopathological complexity of PSP, etiopathogenesis, and emerging biomarkers and well as a review of past and current clinical trials.
Section snippets
Clinicopathologic Complexity of PSP
While several early clinical criteria exist [[23], [24], [25], [26]] the first criteria based on a large autopsy-confirmed series and consensus of experts was performed by Litvan et al., in 1996 (the NINDS-SPSP criteria) which outlined the core clinical features of what is currently known as the PSP-Richardson syndrome (PSP-RS) of a gradual progressive disorder affecting patients over 40 years old with a vertical supranuclear gaze palsy or postural instability and falls within the first year of
Environmental factors
While no single cause of PSP has been identified, a number of environmental and genetic associations have been investigated. The ENGENE-PSP study found that lower educational attainment, exposure to well water and industrial wastes, and firearm use was related to higher risk of developing PSP [61,62]. A cluster of PSP patients was observed in northern France in an area of high industrial waste contamination that also contained heavy metals and an independent study also documented that
Magnetic resonance imaging
Structural neuroimaging biomarkers in PSP include the well described ‘hummingbird sign’ [107], ‘morning glory sign’ [108], or Mickey-Mouse sign [109] all of which result from midbrain atrophy. One study where features of ante mortem MRIs from 48 pathologically-confirmed PSP and MSA cases were compared, 16/22 (73%) of PSP cases could be correctly identified by a radiologist subjectively identifying the ‘hummingbird sign’, with 100% specificity but only 69% sensitivity [109]. Studies that have
Symptomatic pharmacologic therapies
Current pharmacologic therapies for PSP are symptomatic, and tend to show mild to moderate efficacy. Levodopa preparations may be used to treat functionally-impairing bradykinesia and rigidity. In one retrospective study of pathologically confirmed PSP patients, 32% of cases showed a >30% improvement in the Unified Parkinson's Disease Rating Scale and 4% of cases showed levodopa induced dyskinesias [18]. Other studies have documented similar response rates [[156], [157], [158], [159]]; however,
Conclusion
Progressive supranuclear palsy is a complex clinicopathologic entity with diverse clinical manifestations which can led to delays in diagnosis. While the Richardson syndrome is the most indicative of underlying PSP pathology at autopsy, growing understanding of the diverse clinical phenotypes resulting from PSP pathology has led to a significant expansion of the PSP diagnostic criteria aimed at increasing sensitivity of diagnosis. Clinical treatment of PSP is supportive and there is mild to
Authorship contributions
DGC contributed to the drafting the article or revising it critically for important intellectual content, and final approval of the version to be submitted.
IL contributed the drafting the article or revising it critically for important intellectual content, and final approval of the version to be submitted.
Funding
David Coughlin MD is supported by a Clinical Research Training Scholarship in Parkinson's disease grant from the American Academy of Neurology/American Brain Foundation/Parkinson's Foundation (2059). Dr. Litvan is supported by the National Institutes of Health grants: 5P50AG005131-33, 2R01AG038791-06A, U01NS090259, 1U54 NS 092089, U01NS100610, U01NS80818, R25NS098999, P20GM109025; Parkinson Study Group, Michael J Fox Foundation, Lewy Body Association, AVID Pharmaceuticals, Abbvie, Biogen and
Declaration of competing interest
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Coughlin has no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Dr. Litvan’s research is supported in part by Parkinson Study Group, Michael J Fox Foundation, Parkinson Foundation, Lewy Body Association, Roche, Abbvie, Biogen, EIP-Pharma and Biohaven Pharmaceuticals. She was
Acknowledgements
None.
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