De Bartolo Maria Ilenia, Ojha Abhineet, Leodori Giorgio, Piervincenzi Claudia, Vivacqua Giorgio, Pietracupa Sara, Costanzo Matteo, D'Antonio Fabrizia, Barbetti Sonia, Margiotta Roberta, Bruno Giuseppe, Conte Antonella, Berardelli Alfredo, Fabbrini Giovanni, Pantano Patrizia, Belvisi Daniele
From the IRCCS Neuromed (M.I.D.B., G.L., S.P., A.C., A.B., G.F., P.P., D.B.), Pozzilli; Department of Human Neurosciences (A.O., G.L., C.P., S.P., M.C., F.D.A., S.B., R.M., G.B., A.C., A.B., G.F., P.P., D.B.), Sapienza University of Rome; Department of Microscopic and Ultrastructural Anatomy (G.V.), Campus Biomedico University of Rome; Department of Neuroscience (M.C.), Istituto Superiore di Sanità, Rome; and Cognitive and Motor Rehabilitation and Neuroimaging Unit (F.D.A.), IRCCS Fondazione Santa Lucia, Rome, Italy.
Neurology. 2025 Jan 14;104(1):e210192. doi: 10.1212/WNL.0000000000210192. Epub 2024 Dec 19.
According to the dual syndrome hypothesis, patients with Parkinson disease (PD) with visuospatial deficits are more likely to progress to dementia, compared with patients with a prevalent dysexecutive syndrome. In this study, we aimed to investigate whether early connectivity changes in the dorsolateral prefrontal cortex (DLPFC) and the precuneus (PCun)-which are critical to fronto-executive and visuospatial functions, respectively-can identify distinct cognitive phenotypes in cognitively intact newly diagnosed patients with PD.
Newly diagnosed, drug-naïve patients with PD (≤2 years from clinical onset) with normal Montreal Cognitive Assessment (MoCA), were consecutively enrolled from our Movement Disorders Clinics in Italy. Sex-matched and age-matched healthy controls (HCs) were enrolled among nonconsanguineous patients' relatives. Participants underwent 3T-fMRI to investigate resting-state functional connectivity (rs-FC) of DLPFC and PCun with a seed-based approach at baseline (T0). K-means cluster analysis was performed on scores of rs-FC values of patients with PD to identify clusters of patients sharing common patterns of connectivity. Differences in neurophysiologic, motor, and nonmotor scales among PD clusters were assessed at T0 and after a 3.5-year follow-up (T1).
The study included 68 patients with PD (27% women; mean age: 60 ± 9 years; Hoehn & Yahr score: 1.4 ± 0.5; MoCA score: 27.9 ± 1.6) and 31 HCs (39% women; mean age 64.2 ± 9.3 years) at T0. Forty-two patients completed T1 evaluation. Patients displayed reduced rs-FC of both DLPFC and PCun with several cortical and subcortical areas compared with HCs. Cluster 1 was defined by lower values of rs-FC in all investigated regions of interest while clusters 2 and 3, respectively, by higher and intermediate values. Despite none meeting criteria for mild cognitive impairment (MCI) at T0, cluster 1 was older and lower performing in global cognition, fronto-executive, and memory domains, compared with clusters 2 and 3 (all < 0.031). At T1, a more evident worsening in global cognition, fronto-executive, and visuospatial domains and nonmotor and motor symptoms was observed in clusters 1 and 3 vs cluster 2 (all < 0.04), with MCI being more frequent in clusters 1 and 3.
Early connectivity changes of the DLPFC and the PCun occur in newly diagnosed patients with PD without MCI and can distinguish cognitive phenotypes, as confirmed after a longitudinal clinical observation.
根据双重综合征假说，与存在普遍执行功能障碍综合征的帕金森病（PD）患者相比，伴有视觉空间缺陷的PD患者更易发展为痴呆。在本研究中，我们旨在探究背外侧前额叶皮质（DLPFC）和楔前叶（PCun）的早期连接变化——分别对额叶执行功能和视觉空间功能至关重要——能否在认知功能正常的新诊断PD患者中识别出不同的认知表型。
从意大利的运动障碍诊所连续纳入新诊断、未用药（临床发病≤2年）且蒙特利尔认知评估（MoCA）正常的PD患者。在非近亲患者亲属中纳入性别和年龄匹配的健康对照（HCs）。参与者在基线时（T0）接受3T功能磁共振成像（fMRI），采用基于种子点的方法研究DLPFC和PCun的静息态功能连接（rs-FC）。对PD患者的rs-FC值进行K均值聚类分析，以识别具有共同连接模式的患者聚类。在T0和3.5年随访后（T1）评估PD聚类之间神经生理学、运动和非运动量表的差异。
在T0时，该研究纳入了68例PD患者（27%为女性；平均年龄：60±9岁；Hoehn&Yahr评分：1.4±0.5；MoCA评分：27.9±1.6）和31例HCs（39%为女性；平均年龄64.2±9.3岁）。42例患者完成了T1评估。与HCs相比，患者的DLPFC和PCun与多个皮质和皮质下区域的rs-FC均降低。聚类1由所有研究感兴趣区域中较低的rs-FC值定义，而聚类2和3分别由较高和中等值定义。尽管在T0时均未达到轻度认知障碍（MCI）标准，但与聚类2和3相比，聚类1年龄更大，在整体认知、额叶执行功能和记忆领域的表现更低（均P<0.031）。在T1时，与聚类2相比，聚类1和3在整体认知、额叶执行功能和视觉空间领域以及非运动和运动症状方面出现了更明显的恶化（均P<0.04），MCI在聚类1和3中更常见。
DLPFC和PCun的早期连接变化发生在无MCI的新诊断PD患者中，并且可以区分认知表型，纵向临床观察证实了这一点。
