Schönecker Sonja, Brendel Matthias, Palleis Carla, Beyer Leonie, Höglinger Günter U, Schuh Elisabeth, Rauchmann Boris-Stephan, Sauerbeck Julia, Rohrer Guido, Sonnenfeld Stefan, Furukawa Katsutoshi, Ishiki Aiko, Okamura Nobuyuki, Bartenstein Peter, Dieterich Marianne, Bötzel Kai, Danek Adrian, Rominger Axel, Levin Johannes
Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany.
Department of Nuclear Medicine, University Hospital LMU Munich, Munich, Germany.
Front Aging Neurosci. 2019 Sep 11;11:249. doi: 10.3389/fnagi.2019.00249. eCollection 2019.
Neurodegenerative parkinsonian syndromes comprise a number of disorders that are characterized by similar clinical features but are separated on the basis of different pathologies, i.e., aggregates of α-synuclein or tau protein. Due to the overlap of signs and symptoms a precise differentiation is often difficult, especially early in the disease course. Enormous efforts have been taken to develop tau-selective PET imaging agents, but strong off-target binding to monoamine oxidase B (MAO-B) has been observed across first generation ligands. Nonetheless, astrogliosis-related MAO-B elevation is a common histopathological known feature of all parkinsonian syndromes and might be itself an interesting imaging target. Therefore, this study aimed to investigate the performance of [F]-THK5351, a combined MAO-B and tau tracer for differential diagnosis of parkinsonian syndromes. [F]-THK5351 PET was performed in 34 patients: six with Parkinson's disease (PD), nine with multiple system atrophy with predominant parkinsonism (MSA-P), six with MSA with predominant cerebellar ataxia (MSA-C), and 13 with progressive supranuclear palsy (PSP) Richardson's syndrome. Volume-of-interest-based quantification of standardized-uptake-values was conducted in different parkinsonian syndrome-related target regions. PET results were subjected to multinomial logistic regression to create a prediction model discriminating among groups. Furthermore, we correlated tracer uptake with clinical findings. Elevated [F]-THK5351 uptake in midbrain and diencephalon differentiated PSP patients from PD and MSA-C. MSA-C patients were distinguishable by high tracer uptake in the pons and cerebellar deep white matter when compared to PSP and PD patients, whereas MSA-P patients tended to show higher tracer uptake in the lentiform nucleus. A multinomial logistic regression classified 33/34 patients into the correct clinical diagnosis group. Tracer uptake in the pons, cerebellar deep white matter, and striatum was closely associated with the presence of cerebellar and parkinsonian symptoms of MSA patients. The current study demonstrates that combined MAO-B and tau binding of THK5351 facilitates differential diagnosis of parkinsonian syndromes. Furthermore, our data indicate a correlation of MSA phenotype with [F]-THK5351 uptake in certain brain regions, illustrating their relevance for the emergence of clinical symptoms and underlining the potential of THK5351 PET as a biomarker that correlates with pathological changes as well as with disease stage.
神经退行性帕金森综合征包含多种疾病，这些疾病具有相似的临床特征，但基于不同的病理学表现，即α-突触核蛋白或tau蛋白的聚集而相互区分。由于体征和症状存在重叠，精确鉴别往往很困难，尤其是在疾病进程的早期。人们已付出巨大努力来开发tau选择性正电子发射断层扫描（PET）显像剂，但在第一代配体中均观察到与单胺氧化酶B（MAO-B）存在强烈的非靶标结合。尽管如此，星形胶质细胞增生相关的MAO-B升高是所有帕金森综合征常见的组织病理学特征，其本身可能是一个有趣的成像靶点。因此，本研究旨在探讨[F]-THK5351（一种MAO-B和tau联合示踪剂）在帕金森综合征鉴别诊断中的性能。对34例患者进行了[F]-THK5351 PET检查：6例帕金森病（PD）患者、9例以帕金森症状为主的多系统萎缩（MSA-P）患者、6例以小脑性共济失调为主的MSA（MSA-C）患者以及13例进行性核上性麻痹（PSP）理查森综合征患者。在不同帕金森综合征相关靶区进行基于感兴趣区的标准化摄取值定量分析。将PET结果进行多项逻辑回归分析以建立区分不同组别的预测模型。此外，我们将示踪剂摄取与临床发现进行关联分析。中脑和间脑[F]-THK5351摄取升高可将PSP患者与PD和MSA-C患者区分开来。与PSP和PD患者相比，MSA-C患者在脑桥和小脑深部白质的示踪剂摄取较高，而MSA-P患者在豆状核的示踪剂摄取往往较高。多项逻辑回归分析将33/34例患者正确分类到临床诊断组。脑桥、小脑深部白质和纹状体的示踪剂摄取与MSA患者的小脑和帕金森症状密切相关。本研究表明，THK5351对MAO-B和tau的联合结合有助于帕金森综合征的鉴别诊断。此外，我们的数据表明MSA表型与特定脑区的[F]-THK5351摄取相关，这说明了它们与临床症状出现的相关性，并强调了THK5351 PET作为一种与病理变化以及疾病阶段相关的生物标志物的潜力。
