Perra Daniela, Bongianni Matilde, Novi Giovanni, Janes Francesco, Bessi Valentina, Capaldi Stefano, Sacchetto Luca, Tagliapietra Matteo, Schenone Guido, Morbelli Silvia, Fiorini Michele, Cattaruzza Tatiana, Mazzon Giulia, Orrù Christina D, Catalan Mauro, Polverino Paola, Bernardini Andrea, Pellitteri Gaia, Valente Mariarosa, Bertolotti Claudio, Nacmias Benedetta, Maggiore Giandomenico, Cavallaro Tiziana, Manganotti Paolo, Gigli Gianluigi, Monaco Salvatore, Nobili Flavio, Zanusso Gianluigi
Department of Neurosciences, Biomedicine, and Movement Sciences, University of Verona, Policlinico G. B. Rossi, 37134 Verona, Italy.
IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy.
Brain Commun. 2021 Mar 22;3(2):fcab045. doi: 10.1093/braincomms/fcab045. eCollection 2021.
In patients with suspected dementia with Lewy bodies, the detection of the disease-associated α-synuclein in easily accessible tissues amenable to be collected using minimally invasive procedures remains a major diagnostic challenge. This approach has the potential to take advantage of modern molecular assays for the diagnosis of α-synucleinopathy and, in turn, to optimize the recruitment and selection of patients in clinical trials, using drugs directed at counteracting α-synuclein aggregation. In this study, we explored the diagnostic accuracy of α-synuclein real-time quaking-induced conversion assay by testing olfactory mucosa and CSF in patients with a clinical diagnosis of probable ( = 32) or prodromal ( = 5) dementia with Lewy bodies or mixed degenerative dementia (dementia with Lewy bodies/Alzheimer's disease) ( = 6). Thirty-eight patients with non-α-synuclein-related neurodegenerative and non-neurodegenerative disorders, including Alzheimer's disease ( = 10), sporadic Creutzfeldt-Jakob disease ( = 10), progressive supranuclear palsy ( = 8), corticobasal syndrome ( = 1), fronto-temporal dementia ( = 3) and other neurological conditions ( = 6) were also included, as controls. All 81 patients underwent olfactory swabbing while CSF was obtained in 48 participants. At the initial blinded screening of olfactory mucosa samples, 38 out of 81 resulted positive while CSF was positive in 19 samples out of 48 analysed. After unblinding of the results, 27 positive olfactory mucosa were assigned to patients with probable dementia with Lewy bodies, five with prodromal dementia with Lewy bodies and three to patients with mixed dementia, as opposed to three out 38 controls. Corresponding results of CSF testing disclosed 10 out 10 positive samples in patients with probable dementia with Lewy bodies and six out of six with mixed dementia, in addition to three out of 32 for controls. The accuracy among results of real-time quaking-induced conversion assays and clinical diagnoses was 86.4% in the case of olfactory mucosa and 93.8% for CSF. For the first time, we showed that α-synuclein real-time quaking-induced conversion assay detects α-synuclein aggregates in olfactory mucosa of patients with dementia with Lewy bodies and with mixed dementia. Additionally, we provided preliminary evidence that the combined testing of olfactory mucosa and CSF raised the concordance with clinical diagnosis potentially to 100%. Our results suggest that nasal swabbing might be considered as a first-line screening procedure in patients with a diagnosis of suspected dementia with Lewy bodies followed by CSF analysis, as a confirmatory test, when the result in the olfactory mucosa is incongruent with the initial clinical diagnosis.
在疑似路易体痴呆患者中，在易于获取且可通过微创程序采集的组织中检测与疾病相关的α-突触核蛋白仍然是一项重大的诊断挑战。这种方法有可能利用现代分子检测手段来诊断α-突触核蛋白病，进而优化临床试验中患者的招募和选择，这些试验使用旨在对抗α-突触核蛋白聚集的药物。在本研究中，我们通过检测临床诊断为可能（n = 32）或前驱期（n = 5）路易体痴呆或混合性退行性痴呆（路易体痴呆/阿尔茨海默病）（n = 6）患者的嗅黏膜和脑脊液，探索了α-突触核蛋白实时震颤诱导转化检测的诊断准确性。还纳入了38例患有非α-突触核蛋白相关神经退行性和非神经退行性疾病的患者作为对照，包括阿尔茨海默病（n = 10）、散发性克雅氏病（n = 10）、进行性核上性麻痹（n = 8）、皮质基底节综合征（n = 1）、额颞叶痴呆（n = 3）和其他神经系统疾病（n = 6）。所有81例患者均接受了嗅黏膜擦拭取样，48例参与者采集了脑脊液。在对嗅黏膜样本进行初始盲法筛查时，81例中有38例结果呈阳性，而在分析的48例脑脊液样本中有19例呈阳性。结果揭盲后，27例嗅黏膜阳性样本被判定为可能患有路易体痴呆的患者，5例为前驱期路易体痴呆患者，3例为混合性痴呆患者，而38例对照中仅有3例呈阳性。脑脊液检测的相应结果显示，可能患有路易体痴呆的患者中10例样本全部呈阳性，混合性痴呆患者6例全部呈阳性，对照组32例中有3例呈阳性。实时震颤诱导转化检测结果与临床诊断之间的准确率，嗅黏膜为86.4%，脑脊液为93.8%。我们首次表明，α-突触核蛋白实时震颤诱导转化检测可在路易体痴呆和混合性痴呆患者的嗅黏膜中检测到α-突触核蛋白聚集体。此外，我们提供了初步证据，表明嗅黏膜和脑脊液联合检测可能将与临床诊断的一致性提高到100%。我们的结果表明，对于诊断为疑似路易体痴呆的患者，鼻拭子检测可被视为一线筛查程序，随后进行脑脊液分析作为确证性检测，当嗅黏膜检测结果与初始临床诊断不一致时。
