GLUCOCEREBROSIDASE MUTATIONS AND DEMENTIA WITH LEWY BODIES

我们的目标是研究葡萄糖脑苷脂酶（GBA）基因突变是否是路易体痴呆（DLB）的危险因素和生物标志物。GBA最近被证明是帕金森病（PD）的危险因素。在最近的一项对患有DLB、PD、阿尔茨海默病（AD）和没有痴呆的患者的尸检研究中，我们对187个大脑中的GBA基因进行了测序。GBA突变的携带者更有可能患有DLB（发现皮质路易体），即使在存在AD病理（斑块和缠结）的情况下也是如此，尽管他们不太可能患有这种AD病理。相反，AP 0 E-E4患者更有可能患有AD病理学结果，而不太可能患有DLB病理学。因此，正如AP 0 E-E4是AD的风险因素一样，GBA可能是DLB的风险因素和标志物。 在此，我们建议通过对800例具有完整UDS数据、可用DNA和APOE基因型的连续良好表征的ADRC受试者进行GBA基因测序，进一步研究GBA与DLB在活体ADRC受试者中的相关性。我们将：（1）比较携带者和非携带者的疾病诊断和严重程度，DLB中常见的临床症状，包括幻觉、帕金森综合征和波动，以及DLB的神经心理学测试特征，如记忆的相对保留，但皮层下和视觉空间功能受损;（2）比较疾病、症状和神经心理学测试特征，在具有被认为是“轻度”表型的GBA突变的携带者中，即使在纯合子时，（3）在收集的100例ADRC受试者的脑脊液（CSF）中，确定GBA突变携带者（轻度或重度）与非携带者和未受影响的个体相比，CSF中GBA酶活性是否降低。 我们假设GBA突变可能是DLB的标志物，并且GBA活性降低可能易患DLB。我们的研究结果可以提高生活中DLB诊断的准确性，并可能对痴呆患者的诊断和治疗计划具有相关意义。

Our goal is to examine whether mutafions in the glucocerebrosidase (GBA) gene are a risk factor and biomarker for Dementia with Lewy Bodies (DLB). GBA has recently been demonstrated to be a risk factor for Parkinson disease (PD). In a recent autopsy study of pafients with DLB, PD, Alzheimer disease (AD), and without demenfia, we sequenced the GBA gene in each of 187 brains. Carriers of GBA mutations were more likely to have DLB (with findings of cortical Lewy bodies), even in the presence of AD pathology (plaques and tangles), although they were less likely to have such AD pathology. Conversely, those with AP0E-E4 were more likely to have AD pathological findings, and less likely to have DLB pathology. Thus, just as AP0E-E4 is a risk factor for AD, it is possible that GBA is a risk factor and marker for DLB. Here we propose to further study the relafion of GBA to DLB in living ADRC subjects by sequencing the GBA gene in 800 consecutive well-characterized ADRC subjects with full UDS data, and available DNA, and APOE genotype. We will: (1) compare carriers and non-carriers for disease diagnosis and severity, for clinical symptoms common in DLB including hallucinafions, parkinsonism, and fluctuations, and for neuropsychological test characteristics of DLB, such as relative preservation of memory, but impaired subcortical and visuospatial funcfion; (2) compare disease, symptoms, and neuropsychological test characteristics, in carriers who have GBA mutations thought to be of "mild" phenotype even when homozygous, to those carrying mutafions known to be of "severe" phenotype when homozygous; (3) determine in the collected cerebrospinal fluid (CSF) of 100 ADRC subjects whether there is decreased GBA enzymafic activity in CSF of patients who are GBA mutation carriers of mild type or severe type, versus noncarriers, and in unaffected individuals. We hypothesize that GBA mutations may be a marker for DLB, and that decreased GBA activity may predispose to DLB. Our results may allow improved accuracy of diagnosis of DLB during life, and may have related implicafions on making prognosfic statements and treatment plans for patients with dementia.