Labrador-Espinosa Miguel A, Silva-Rodriguez Jesús, Okkels Niels, Muñoz-Delgado Laura, Horsager Jacob, Castro-Labrador Sandra, Franco-Rosado Pablo, Castellano-Guerrero Ana María, Iglesias-Camacho Elena, San-Eufrasio Manuela, Macías-García Daniel, Jesús Silvia, Adarmes-Gómez Astrid, Ojeda-Lepe Elena, Carrillo Fátima, Martín-Rodríguez Juan Francisco, Roldan Lora Florinda, García-Solís David, Borghammer Per, Mir Pablo, Grothe Michel J
Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/Universidad de Sevilla/CSIC/CIBERNED, Sevilla, Spain.
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
Mol Psychiatry. 2025 Jun;30(6):2372-2380. doi: 10.1038/s41380-024-02842-9. Epub 2024 Dec 5.
Cortical hypometabolism on FDG-PET is a well-established neuroimaging biomarker of cognitive impairment in Parkinson's disease (PD), but its pathophysiologic origins are incompletely understood. Cholinergic basal forebrain (cBF) degeneration is a prominent pathological feature of PD-related cognitive impairment and may contribute to cortical hypometabolism through cholinergic denervation of cortical projection areas. Here, we investigated in-vivo associations between subregional cBF volumes on 3T-MRI, cortical hypometabolism on [F]FDG-PET, and cognitive deficits in a cohort of 95 PD participants with varying degrees of cognitive impairment. We further assessed the spatial correspondence of the cortical pattern of cBF-associated hypometabolism with the pattern of cholinergic denervation in PD as assessed by [F]FEOBV-PET imaging of presynaptic cholinergic terminal density in a second cohort. Lower volume of the cortically-projecting posterior cBF, but not of the anterior cBF, was significantly associated with extensive neocortical hypometabolism [p(FDR) < 0.05], which mediated the association between cBF atrophy and cognitive impairment (mediated proportion: 43%, p < 0.001). In combined models, posterior cBF atrophy explained more variance in cortical hypometabolism (R = 0.26, p < 0.001) than local atrophy in the cortical areas themselves (R = 0.16, p = 0.01). Topographic correspondence analysis with the [F]FEOBV-PET pattern revealed that cortical areas showing most pronounced cBF-associated hypometabolism correspond to those showing most severe cholinergic denervation in PD (Spearman's ρ = 0.57, p < 0.001). In conclusion, posterior cBF atrophy in PD is selectively associated with hypometabolism in denervated cortical target areas, which mediates the effect of cBF atrophy on cognitive impairment. These data provide first-time in-vivo evidence that cholinergic degeneration represents a principle pathological correlate of cortical hypometabolism underlying cognitive impairment in PD.
氟代脱氧葡萄糖正电子发射断层扫描（FDG-PET）显示的皮质低代谢是帕金森病（PD）认知障碍中一种公认的神经影像学生物标志物，但其病理生理起源尚未完全明确。胆碱能基底前脑（cBF）变性是PD相关认知障碍的一个突出病理特征，可能通过皮质投射区域的胆碱能去神经支配导致皮质低代谢。在此，我们在95名不同程度认知障碍的PD参与者队列中，研究了3T磁共振成像（MRI）上cBF亚区域体积、[F]FDG-PET上的皮质低代谢与认知缺陷之间的体内关联。我们还在第二个队列中，通过对突触前胆碱能终末密度进行[F]FEOBV-PET成像，评估了PD中cBF相关低代谢的皮质模式与胆碱能去神经支配模式的空间对应关系。皮质投射的后cBF体积降低，而非前cBF体积降低，与广泛的新皮质低代谢显著相关[p（FDR）<0.05]，这介导了cBF萎缩与认知障碍之间的关联（介导比例：43%，p<0.001）。在联合模型中，后cBF萎缩比皮质区域自身的局部萎缩能解释更多皮质低代谢的方差（R=0.26，p<0.001），而局部萎缩的解释力为（R=0.16，p=0.01）。与[F]FEOBV-PET模式的地形对应分析显示，PD中显示最明显cBF相关低代谢的皮质区域与显示最严重胆碱能去神经支配的区域相对应（斯皮尔曼ρ=0.57，p<0.001）。总之，PD中的后cBF萎缩与去神经支配的皮质靶区域低代谢选择性相关，这介导了cBF萎缩对认知障碍的影响。这些数据首次提供了体内证据，表明胆碱能变性是PD认知障碍潜在皮质低代谢的主要病理相关因素。
