Amsterdam UMC, Vrije Universiteit Amsterdam, Dept. of Anatomy and Neurosciences, Amsterdam Neuroscience, Amsterdam, the Netherlands.
Erasmus MC, University Medical Center Rotterdam, Dept. of Neurology and Alzheimer Center, Rotterdam, the Netherlands.
Parkinsonism Relat Disord. 2019 Jun;63:162-168. doi: 10.1016/j.parkreldis.2019.02.011. Epub 2019 Feb 13.
The disease course of dementia with Lewy bodies (DLB) can be rapidly progressive, clinically resembling Creutzfeldt-Jakob's disease (CJD). To better understand factors contributing to this rapidly progressive disease course, we describe load and distribution of neuropathology, and the presence of possible disease-associated genetic defects in a post-mortem series of DLB cases clinically suspected of CJD.
We included pathologically confirmed DLB cases with a disease duration of 3.5 years or less from the Dutch Surveillance Center for Prion Diseases, collected between 1998 and 2014. Lewy body disease (LBD) and Alzheimer's disease (AD)-related pathology were staged and semi-quantitatively scored in selected brain regions. Whole exome sequencing analysis of known disease-associated genes, copy number analysis, APOE ε genotyping and C9orf72 repeat expansion analysis were performed to identify defects in genes with a well-established involvement in Parkinson's disease or AD.
Diffuse LBD was present in nine cases, transitional LBD in six cases and brainstem-predominant LBD in one case. Neocortical alpha-synuclein load was significantly higher in cases with intermediate-to-high than in cases with low-to-none AD-related pathology (p = 0.007). We found two GBA variants (p.D140H and p.E326K) in one patient and two heterozygous rare variants of unknown significance in SORL1 in two patients.
A high load of neocortical alpha-synuclein pathology was present in most, but not all DLB cases. Additional burden from presence of concomitant pathologies, synergistic effects and specific genetic defects in the known disease-associated genes may have contributed to the rapid disease progression.
路易体痴呆（DLB）的疾病过程可能进展迅速，临床上类似于克雅氏病（CJD）。为了更好地了解导致这种快速进展疾病过程的因素，我们描述了神经病理学的负荷和分布，以及在一组临床上疑似 CJD 的 DLB 病例的死后系列中可能与疾病相关的遗传缺陷的存在。
我们纳入了荷兰朊病毒疾病监测中心确认的、病程在 3.5 年或更短的病理证实的 DLB 病例，收集时间为 1998 年至 2014 年。在选定的脑区对路易体病（LBD）和阿尔茨海默病（AD）相关的病理学进行分期和半定量评分。对已知与帕金森病或 AD 有明确关联的基因进行全外显子组测序分析、拷贝数分析、APOE ε 基因型分析和 C9orf72 重复扩增分析，以确定在基因中存在缺陷与帕金森病或 AD 有明确关联。
弥漫性 LBD 见于 9 例，过渡性 LBD 见于 6 例，脑干为主的 LBD 见于 1 例。与低至无 AD 相关病理学相比，中至高 AD 相关病理学的病例中，新皮质的α-突触核蛋白负荷明显更高（p=0.007）。我们在 1 例患者中发现了 2 种 GBA 变异（p.D140H 和 p.E326K），在 2 例患者中发现了 2 种 SORL1 的杂合性罕见意义不明的变异。
大多数（但不是全部）DLB 病例存在高负荷的新皮质α-突触核蛋白病理学。同时存在的伴发病理、协同作用以及已知与疾病相关基因中的特定遗传缺陷的额外负担可能导致疾病的快速进展。
