Protracted course progressive supranuclear palsy

• Published in: European journal of neurology Vol. 29; no. 8; pp. 2220 - 2231
• Main Authors: Couto, Blas, Martinez‐Valbuena, Ivan, Lee, Seojin, Alfradique‐Dunham, Isabel, Perrin, Richard J., Perlmutter, Joel S., Cruchaga, Carlos, Kim, Ain, Visanji, Naomi, Sato, Christine, Rogaeva, Ekaterina, Lang, Anthony E., Kovacs, Gabor G.
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.08.2022
• Subjects: Alleles; Atrophy; Basal ganglia; Central nervous system diseases; Cognitive ability; Disease Progression; Gait; Gene polymorphism; Genetic analysis; Glucose Transport Proteins, Facilitative - genetics; Haplotypes; Humans; microglia; Movement disorders; Neurodegenerative diseases; Nucleotides; pallidonigroluysian atrophy; Paralysis; Parkinsonian disorders; Parkinsonian Disorders - pathology; Pathology; Phenotypes; Polymorphism; Polymorphism, Single Nucleotide; prognosis; Progressive supranuclear palsy; Protein folding; Protein seeding; Retrospective Studies; Richardson syndrome; Single-nucleotide polymorphism; Supranuclear Palsy, Progressive - pathology; Tau protein; tau Proteins - metabolism; Tauopathies - pathology; Tripartite Motif Proteins - genetics; Ubiquitin-Protein Ligases - genetics; Parkinsonian disorders; microglia; pallidonigroluysian atrophy; prognosis; tau protein; Richardson syndrome; progressive supranuclear palsy
• ISSN: 1351-5101; 1468-1331
• DOI: 10.1111/ene.15346

Background and purpose Progressive supranuclear palsy (PSP) encompasses a broader range of disease courses than previously appreciated. The most frequent clinical presentations of PSP are Richardson syndrome (RS) and PSP with a predominant Parkinsonism phenotype (PSP‐P). Time to reach gait dependence and cognitive impairment have been proposed as prognostic disease milestones. Genetic polymorphisms in TRIM11 and SLC2A13 genes have been associated with longer disease duration (DD). Methods Methods used include retrospective chart review, genetic single nucleotide polymorphism analyses (in three cases), and neuropathology. Results We identified four cases with long (>10–15 years) or very long (>15 years) DD. Stage 1 PSP tau pathology was present in two cases (one PSP‐P and one undifferentiated phenotype), whereas pallidonigroluysian atrophy (PSP‐RS) and Stage 4/6 (PSP‐P) PSP pathology were found in the other two cases. Three cases were homozygous for the rs564309‐C allele of the TRIM11 gene and the H1 MAPT haplotype. Two were heterozygous for rs2242367 (G/A) in SLC2A13, whereas the third was homozygous for the G‐allele. Conclusions We propose a protracted course subtype of PSP (PC‐PSP) based on clinical or neuropathological criteria in two cases with anatomically restricted PSP pathology, and very long DD and slower clinical progression in the other two cases. The presence of the rs564309‐C allele may influence the protracted disease course. Crystallizing the concept of PC‐PSP is important to further understand the pathobiology of tauopathies in line with current hypotheses of protein misfolding, seeding activity, and propagation. Here, we propose to define protracted course of progressive supranuclear palsy (PSP) based on clinical or neuropathological criteria. We present four cases: two cases with anatomically restricted PSP pathology, and two cases with very long disease duration and slower clinical progression. We believe that crystallizing the concept of protracted PSP is important to further understand the pathobiology of tauopathies in line with current hypotheses of protein misfolding, seeding activity, and propagation.