Creese Byron, Bell Emily, Johar Iskandar, Francis Paul, Ballard Clive, Aarsland Dag
University of Exeter Medical School, University of Exeter, Exeter, UK.
Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Am J Med Genet B Neuropsychiatr Genet. 2018 Mar;177(2):232-241. doi: 10.1002/ajmg.b.32549. Epub 2017 May 26.
Heterozygous mutations in glucocerebrosidase gene (GBA) are a major genetic risk factor for Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Recently, there has been a considerable focus on the relationship between GBA mutations and emergence of cognitive impairment and neuropsychiatric symptoms in these diseases. Here, we review the literature in this area, with a particular focus, including meta-analysis, on the key neuropsychiatric symptoms of cognitive impairment, psychosis, and depression in Parkinson's disease. Our meta-analysis demonstrated that GBA mutations are associated with a 2.4-fold increased risk of cognitive impairment. In addition, our novel meta-analyses of psychosis and depression showed a 1.8- and 2.2-fold increased risk respectively associated with GBA mutations, although due to possible bias and heterogeneity the depression findings should be interpreted with caution. While the precise mechanisms which increase susceptibility to neurodegeneration in GBA carriers are not known, evidence of greater cortical Lewy body pathology, reduced patterns of cortical activation, and hippocampal pathology in animal models are all consistent with a direct effect of GBA mutations on these symptoms. Extension of this work in DLB and individuals without neurodegeneration will be important in further characterizing how GBA mutations increase risk for PD and DLB and influence disease course.
葡萄糖脑苷脂酶基因（GBA）的杂合突变是帕金森病（PD）和路易体痴呆（DLB）的主要遗传风险因素。最近，人们相当关注GBA突变与这些疾病中认知障碍和神经精神症状出现之间的关系。在此，我们回顾该领域的文献，特别关注包括荟萃分析在内的帕金森病认知障碍、精神病和抑郁等关键神经精神症状。我们的荟萃分析表明，GBA突变与认知障碍风险增加2.4倍相关。此外，我们对精神病和抑郁的新荟萃分析显示，GBA突变分别与风险增加1.8倍和2.2倍相关，不过由于可能存在的偏倚和异质性，抑郁方面的研究结果应谨慎解读。虽然尚不清楚GBA携带者对神经退行性变易感性增加的确切机制，但动物模型中更多皮质路易体病理改变、皮质激活模式减少以及海马病理改变的证据均与GBA突变对这些症状的直接影响相一致。在DLB和无神经退行性变的个体中扩展这项工作，对于进一步明确GBA突变如何增加PD和DLB风险以及影响疾病进程将具有重要意义。
