Ivleva Elena I, Clementz Brett A, Dutcher Anthony M, Arnold Sara J M, Jeon-Slaughter Haekyung, Aslan Sina, Witte Bradley, Poudyal Gaurav, Lu Hanzhang, Meda Shashwath A, Pearlson Godfrey D, Sweeney John A, Keshavan Matcheri S, Tamminga Carol A
University of Texas Southwestern Medical Center, Dallas.
University of Georgia, Athens, Georgia.
Biol Psychiatry. 2017 Jul 1;82(1):26-39. doi: 10.1016/j.biopsych.2016.08.030. Epub 2016 Aug 31.
The current definitions of psychotic illness lack biological validity, motivating alternative biomarker-driven disease entities. Building on experimental constructs-Biotypes-that were previously developed from cognitive and neurophysiologic measures, we contrast brain anatomy characteristics across Biotypes alongside conventional diagnoses, examining gray matter density (GMD) as an independent validator for the Biotypes.
Whole brain GMD measures were examined in probands, their relatives, and healthy subjects organized by Biotype and then by DSM-IV-TR diagnosis (n = 1409) using voxel-based morphometry with subsequent subject-level regional characterization and distribution analyses.
Probands grouped by Biotype versus healthy controls showed a stepwise pattern of GMD reductions as follows: Biotype1, extensive and diffusely distributed GMD loss, with the largest effects in frontal, anterior/middle cingulate cortex, and temporal regions; Biotype2, intermediate and more localized reductions, with the largest effects in insula and frontotemporal regions; and Biotype3, small reductions localized to anterior limbic regions. Relatives showed regionally distinct GMD reductions versus healthy controls, with primarily anterior (frontotemporal) effects in Biotype1; posterior (temporo-parieto-cerebellar) in Biotype2; and normal GMD in Biotype3. Schizophrenia and schizoaffective probands versus healthy controls showed overlapping GMD reductions, with the largest effects in frontotemporal and parietal regions; psychotic bipolar probands had small reductions, primarily in frontal regions. GMD changes in relatives followed regional patterns observed in probands, albeit less extensive. Biotypes showed stronger between-group separation based on GMD than the conventional diagnoses and were the strongest predictor of GMD change.
GMD biomarkers depicted unique brain structure characteristics within Biotypes, consistent with their cognitive and sensorimotor profiles, and provided stronger discrimination for biologically driven biotypes than symptom-based diagnoses.
目前对精神病性疾病的定义缺乏生物学效度，这促使人们寻求基于生物标志物的替代性疾病实体。基于先前从认知和神经生理学测量中得出的实验性结构——生物型，我们将生物型与传统诊断方法相结合，对比了不同生物型的脑解剖特征，并将灰质密度（GMD）作为生物型的独立验证指标进行研究。
采用基于体素的形态测量法，对先证者、其亲属以及按生物型和DSM-IV-TR诊断分类的健康受试者（n = 1409）进行全脑GMD测量，随后进行个体水平的区域特征分析和分布分析。
按生物型分组的先证者与健康对照相比，GMD降低呈现出逐步变化的模式，具体如下：生物型1，广泛且弥漫性分布的GMD损失，额叶、前/中扣带回皮质和颞叶区域受影响最大；生物型2，中度且更局限的降低，岛叶和额颞叶区域受影响最大；生物型3，仅在前边缘区域有小幅度降低。亲属与健康对照相比，GMD降低具有区域差异，生物型1主要在前部（额颞叶），生物型2在后部（颞顶小脑），生物型3的GMD正常。精神分裂症和分裂情感性障碍先证者与健康对照相比，GMD降低有重叠，额颞叶和顶叶区域受影响最大；精神病性双相障碍先证者降低幅度较小，主要在额叶区域。亲属的GMD变化遵循先证者中观察到的区域模式，只是程度较轻。基于GMD，生物型之间的组间分离比传统诊断更强，并且是GMD变化的最强预测指标。
GMD生物标志物描绘了生物型内独特的脑结构特征，与其认知和感觉运动特征一致，并且相较于基于症状的诊断，能为基于生物学的生物型提供更强的区分度。
