McMillan Corey T, Wolk David A
Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
J Neurol Neurosurg Psychiatry. 2016 Oct;87(10):1112-22. doi: 10.1136/jnnp-2015-312690. Epub 2016 Jun 9.
To evaluate the frequency of cerebral amyloid in early Parkinson's disease (ePD) and provide a multimodal assessment of the influence of cerebral amyloid on disease phenotype.
We performed a multicentre cohort study of the Parkinson's Progression Markers Initiative (PPMI), including 369 drug-naïve patients with ePD and 174 healthy controls (HC). Cerebrospinal fluid (CSF) amyloid-β levels were transformed using the linear regression procedure. A cut-off of >198 pg/mL was used to define amyloid-negative (PD-) and amyloid-positive (PD+) subgroups. Grey matter (GM) density and hippocampal volume from the MRI was measured using Advanced Normalisation Tools (ANTs). We compared demographic, genetic, CSF, behavioural, functional and imaging modalities across ePD- and ePD+ groups.
We observed that 16.5% of ePD have CSF evidence of amyloidosis. PD+ was significantly older than PD-, had a higher frequency of APOE e4 alleles and all CSF measures (total-tau, phosphorylated-tau and α-synuclein) were reduced. PD+ had reduced cognitive performance relative to PD- on Symbol-Digit Matching, Verbal Category Fluency and Delayed Recall tests. Imaging analysis in a subset of individuals (PD+ =43; PD- =241) revealed overlapping GM atrophy relative to HC in medial temporal, frontal and brainstem structures. Direct comparisons revealed PD+ GM reductions predominantly located in the frontal cortex while PD- had GM reductions in subcortical structures. These observations remain when controlling for age and APOE e4 allele status.
Cerebral amyloid in ePD yields a unique phenotype across all measured modalities that is consistent with a synergistic interaction between α-synuclein and amyloid pathology. Amyloid status should be considered when screening these individuals for trials involving disease-modifying agents.
评估早期帕金森病（ePD）中脑淀粉样蛋白的频率，并对脑淀粉样蛋白对疾病表型的影响进行多模态评估。
我们对帕金森病进展标志物倡议（PPMI）进行了一项多中心队列研究，包括369例未服用药物的ePD患者和174例健康对照（HC）。使用线性回归程序对脑脊液（CSF）淀粉样蛋白-β水平进行转换。使用>198 pg/mL的临界值来定义淀粉样蛋白阴性（PD-）和淀粉样蛋白阳性（PD+）亚组。使用高级归一化工具（ANTs）测量MRI的灰质（GM）密度和海马体积。我们比较了ePD-组和ePD+组在人口统计学、遗传学、CSF、行为、功能和影像学方面的差异。
我们观察到16.5%的ePD患者有CSF淀粉样变性的证据。PD+组比PD-组年龄显著更大，APOE e4等位基因频率更高，所有CSF指标（总tau蛋白、磷酸化tau蛋白和α-突触核蛋白）均降低。在符号数字匹配、语言类别流畅性和延迟回忆测试中，PD+组相对于PD-组认知表现下降。对一部分个体（PD+ =43；PD- =241）的影像学分析显示，相对于HC，内侧颞叶、额叶和脑干结构存在重叠的GM萎缩。直接比较显示，PD+组的GM减少主要位于额叶皮质，而PD-组的GM减少位于皮质下结构。在控制年龄和APOE e4等位基因状态后，这些观察结果仍然成立。
ePD中的脑淀粉样蛋白在所有测量模式下产生独特的表型，这与α-突触核蛋白和淀粉样蛋白病理之间的协同相互作用一致。在对这些个体进行涉及疾病修饰药物的试验筛查时，应考虑淀粉样蛋白状态。
