Institute of Neuroscience and Institute for Ageing, Newcastle University, Campus for Ageing and Vitality, NE4 5PL, Newcastle upon Tyne, UK.
Acta Neuropathol. 2015 May;129(5):729-48. doi: 10.1007/s00401-015-1406-3. Epub 2015 Mar 11.
Multiple different pathological protein aggregates are frequently seen in human postmortem brains and hence mixed pathology is common. Mixed dementia on the other hand is less frequent and neuropathologically should only be diagnosed if criteria for more than one full blown disease are met. We quantitatively measured the amount of hyperphosphorylated microtubule associated tau (HP-τ), amyloid-β protein (Aβ) and α-synuclein (α-syn) in cases that were neuropathologically diagnosed as mixed Alzheimer's disease (AD) and neocortical Lewy body disease (LBD) but clinically presented either as dementia due to AD or LBD, the latter including dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). Our study group consisted of 28 cases (mean age, 76.11 SE: ±1.29 years; m:f, 17:11) of which 19 were neuropathologically diagnosed as mixed AD/DLB. Clinically, 8 mixed AD/DLB cases were diagnosed as AD (cAD), 8 as DLB (cDLB) and 3 as PDD (cPDD). In addition, we investigated cases that were both clinically and neuropathologically diagnosed as either AD (pure AD; n = 5) or DLB/neocortical LBD (pure DLB; n = 4). Sections from neocortical, limbic and subcortical areas were stained with antibodies against HP-τ, Aβ and α-syn. The area covered by immunopositivity was measured using image analysis. cAD cases had higher HP-τ loads than both cDLB and cPDD and the distribution of HP-τ in cAD was similar to the one observed in pure AD whilst cDLB showed comparatively less hippocampal HP-τ load. cPDD cases showed lower HP-τ and Aβ loads and higher α-syn loads. Here, we show that in neuropathologically mixed AD/DLB cases both the amount and the topographical distribution of pathological protein aggregates differed between distinct clinical phenotypes. Large-scale clinicopathological correlative studies using a quantitative methodology are warranted to further elucidate the neuropathological correlate of clinical symptoms in cases with mixed pathology.
在人类死后的大脑中经常可以看到多种不同的病理性蛋白聚集物，因此混合病理学很常见。另一方面，混合性痴呆症较少见，只有在符合一种以上完全性疾病的标准时才能进行神经病理学诊断。我们定量测量了在神经病理学上被诊断为混合性阿尔茨海默病（AD）和新皮质路易体病（LBD）的病例中，高度磷酸化微管相关tau（HP-τ）、淀粉样β蛋白（Aβ）和α-突触核蛋白（α-syn）的含量，这些病例在临床上表现为 AD 或 LBD 引起的痴呆，但后者包括路易体痴呆（DLB）和帕金森病痴呆（PDD）。我们的研究组由 28 例病例组成（平均年龄，76.11 SE：±1.29 岁；男：女，17：11），其中 19 例被神经病理学诊断为混合性 AD/DLB。临床上，8 例混合性 AD/DLB 被诊断为 AD（cAD），8 例为 DLB（cDLB），3 例为 PDD（cPDD）。此外，我们还研究了既在临床上又在神经病理学上被诊断为 AD（纯 AD；n=5）或 DLB/新皮质 LBD（纯 DLB；n=4）的病例。使用针对 HP-τ、Aβ 和 α-syn 的抗体对新皮质、边缘和皮质下区域的切片进行染色。使用图像分析测量免疫阳性区域的覆盖面积。cAD 病例的 HP-τ 负荷高于 cDLB 和 cPDD，cAD 的 HP-τ 分布与纯 AD 观察到的分布相似，而 cDLB 显示出相对较低的海马 HP-τ 负荷。cPDD 病例的 HP-τ 和 Aβ 负荷较低，α-syn 负荷较高。在这里，我们表明在神经病理学上混合性 AD/DLB 病例中，不同临床表型之间病理蛋白聚集物的数量和拓扑分布存在差异。需要进行大规模的临床病理相关性研究，使用定量方法进一步阐明混合性病变病例中临床症状的神经病理学相关性。
