Cortical hypometabolism in Parkinson’s disease is linked to cholinergic basal forebrain atrophy

IF 9.6 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Psychiatry Pub Date : 2024-12-05 DOI:10.1038/s41380-024-02842-9
Miguel A. Labrador-Espinosa, Jesús Silva-Rodriguez, Niels Okkels, Laura Muñoz-Delgado, Jacob Horsager, Sandra Castro-Labrador, Pablo Franco-Rosado, Ana María Castellano-Guerrero, Elena Iglesias-Camacho, Manuela San-Eufrasio, Daniel Macías-García, Silvia Jesús, Astrid Adarmes-Gómez, Elena Ojeda-Lepe, Fátima Carrillo, Juan Francisco Martín-Rodríguez, Florinda Roldan Lora, David García-Solís, Per Borghammer, Pablo Mir, Michel J. Grothe
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Abstract

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 [18F]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 [18F]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 (R2 = 0.26, p < 0.001) than local atrophy in the cortical areas themselves (R2 = 0.16, p = 0.01). Topographic correspondence analysis with the [18F]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.

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帕金森病的皮质代谢降低与胆碱能性基底前脑萎缩有关
FDG-PET的皮质代谢低下是帕金森病(PD)认知障碍的一种公认的神经成像生物标志物,但其病理生理起源尚不完全清楚。基底前脑胆碱能变性(cBF)是pd相关认知障碍的一个重要病理特征,可能通过皮质投射区胆碱能失神经支配导致皮质代谢降低。在这里,我们研究了95名患有不同程度认知障碍的PD参与者在3T-MRI上的分区域cBF体积、[18F]FDG-PET上的皮质低代谢和认知缺陷之间的体内关联。我们在第二组队列中通过[18F]FEOBV-PET突触前胆碱能末端密度成像进一步评估了脑血流相关低代谢的皮质模式与PD中胆碱能失神经控制模式的空间对应关系。脑后皮质突出区体积较低与广泛的新皮质低代谢显著相关[p(FDR) < 0.05],这介导了脑后皮质萎缩和认知障碍之间的关联(介导比例:43%,p < 0.001)。在联合模型中,脑皮质后部萎缩比皮质局部萎缩更能解释皮质代谢低下(R2 = 0.26, p < 0.001)的差异(R2 = 0.16, p = 0.01)。与[18F]FEOBV-PET模式的地形对应分析显示,在PD中表现出最明显的cbf相关低代谢的皮质区域与表现出最严重的胆碱能失神经支配的皮质区域相对应(Spearman 's ρ = 0.57, p < 0.001)。综上所述,PD后脑皮质萎缩与失神经皮质靶区代谢降低选择性相关,从而介导脑皮质萎缩对认知功能障碍的影响。这些数据首次提供了体内证据,证明胆碱能变性是帕金森病患者认知障碍基础上皮层代谢低下的主要病理关联。
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来源期刊
Molecular Psychiatry
Molecular Psychiatry 医学-精神病学
CiteScore
20.50
自引率
4.50%
发文量
459
审稿时长
4-8 weeks
期刊介绍: Molecular Psychiatry focuses on publishing research that aims to uncover the biological mechanisms behind psychiatric disorders and their treatment. The journal emphasizes studies that bridge pre-clinical and clinical research, covering cellular, molecular, integrative, clinical, imaging, and psychopharmacology levels.
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