Department of Neurology, Memory and Aging Center, University of California San Francisco, San Francisco, CA, USA.
Department of Neurology, Memory and Aging Center, University of California San Francisco, San Francisco, CA, USA.
Neuroimage Clin. 2019;23:101822. doi: 10.1016/j.nicl.2019.101822. Epub 2019 Apr 10.
We aimed to understand the impact of dopamine receptor D (DRD) polymorphisms on neurodegeneration in patients with dementia. We hypothesized that DRDdampened-variants with reduced functional potency would be associated with greater atrophy in regions with higher receptor density. Given that DRD is concentrated in anterior regions of the limbic and cortical forebrain we anticipated genotype effects in patients with a more rostral pattern of neurodegeneration.
337 subjects, including healthy controls, patients with Alzheimer's disease (AD) and frontotemporal dementia (FTD) underwent genotyping, structural MRI, and cognitive/behavioral testing. We conducted whole-brain voxel-based morphometry to examine the relationship between DRD genotypes and brain atrophy patterns within and across groups. General linear modeling was used to evaluate relationships between genotype and cognitive/behavioral measures.
DRD dampened-variants predicted gray matter atrophy in disease-specific regions of FTD in anterior cingulate, ventromedial prefrontal, orbitofrontal and insular cortices on the right greater than the left. Genotype predicted greater apathy and repetitive motor disturbance in patients with FTD. These results covaried with frontoinsular cortical atrophy. Peak atrophy patterned along regions of neuroanatomic vulnerability in FTD-spectrum disorders. In AD subjects and controls, genotype did not impact gray matter intensity.
We conclude that DRD polymorphisms with reduced functional potency exacerbate neuronal injury in sites of higher receptor density, which intersect with syndrome-specific regions undergoing neurodegeneration in FTD.
我们旨在了解多巴胺受体 D (DRD) 多态性对痴呆患者神经退行性变的影响。我们假设，功能效力降低的 DRD 减敏变体与受体密度较高的区域的更大萎缩有关。鉴于 DRD 集中在前脑边缘和皮质的前部区域，我们预计在具有更靠前的神经退行性变模式的患者中会出现基因型效应。
337 名受试者，包括健康对照、阿尔茨海默病 (AD) 和额颞叶痴呆 (FTD) 患者，进行了基因分型、结构 MRI 和认知/行为测试。我们进行了全脑体素形态计量学研究，以检查 DRD 基因型与各组内和组间大脑萎缩模式之间的关系。使用一般线性模型评估基因型与认知/行为测量之间的关系。
DRD 减敏变体预测了 FTD 患者前扣带回、腹内侧前额叶、眶额和岛叶皮质等疾病特异性区域的灰质萎缩，右侧大于左侧。基因型预测 FTD 患者的冷漠和重复运动障碍更大。这些结果与额岛皮质萎缩相关。萎缩的峰值沿着 FTD 谱系障碍的神经解剖脆弱区域排列。在 AD 患者和对照组中，基因型不会影响灰质强度。
我们得出结论，功能效力降低的 DRD 多态性会加剧高受体密度部位的神经元损伤，这些部位与 FTD 中发生神经退行性变的综合征特异性区域相交。
