Edmond J. Safra Program in Parkinson's Disease, Rossy Program for PSP Research and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, Toronto, Ontario, Canada.
Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, Canada.
Eur J Neurol. 2022 Aug;29(8):2220-2231. doi: 10.1111/ene.15346. Epub 2022 Apr 21.
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 used include retrospective chart review, genetic single nucleotide polymorphism analyses (in three cases), and neuropathology.
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.
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.
进行性核上性麻痹（PSP）的疾病过程比之前认为的更为广泛。PSP 最常见的临床表现为 Richardson 综合征（RS）和以帕金森病为主的 PSP（PSP-P）。达到步态依赖和认知障碍的时间已被提出作为预测疾病的里程碑。TRIM11 和 SLC2A13 基因的遗传多态性与较长的疾病持续时间（DD）有关。
使用的方法包括回顾性图表审查、基因单核苷酸多态性分析（在三个案例中）和神经病理学。
我们发现了四个具有长（>10-15 年）或非常长（>15 年）DD 的病例。两个病例存在 1 期 PSP tau 病理学（一个 PSP-P 和一个未分化表型），而另外两个病例存在苍白球黑质路易体萎缩（PSP-RS）和 4/6 期（PSP-P）PSP 病理学。三个病例为 TRIM11 基因 rs564309-C 等位基因和 H1 MAPT 单倍型的纯合子，两个为 SLC2A13 中 rs2242367（G/A）的杂合子，而第三个为 G 等位基因的纯合子。
我们根据两个具有解剖学限制 PSP 病理学的病例的临床或神经病理学标准，提出了一种 PSP 的迁延病程亚型（PC-PSP），并在另外两个病例中提出了非常长的 DD 和更缓慢的临床进展。rs564309-C 等位基因的存在可能影响迁延性疾病过程。确定 PC-PSP 的概念对于进一步了解与蛋白质错误折叠、种子活性和传播的当前假说相一致的 tau 病的病理生物学非常重要。
