Josephs Keith A, Murray Melissa E, Whitwell Jennifer L, Tosakulwong Nirubol, Weigand Stephen D, Petrucelli Leonard, Liesinger Amanda M, Petersen Ronald C, Parisi Joseph E, Dickson Dennis W
Department of Neurology, Division of Behavioral Neurology, Mayo Clinic, Rochester, 55905, MN, USA.
Department of Neurology, Division of Movement Disorders, Mayo Clinic, Rochester, MN, 55905, USA.
Acta Neuropathol. 2016 Apr;131(4):571-85. doi: 10.1007/s00401-016-1537-1. Epub 2016 Jan 25.
In this study, we update the TDP-43 in Alzheimer's disease staging scheme by assessing the topography of TDP-43 in 193 cases of Alzheimer's disease, in 14 different brain regions (eight previously described plus six newly reported) and use conditional probability to model the spread of TDP-43 across the 14 brain regions. We show that in addition to the eight original regions we previously reported [amygdala, entorhinal cortex, subiculum, dentate gyrus of the hippocampus, occipitotemporal cortex, inferior temporal cortex, middle frontal cortex and basal ganglia (putamen/globus pallidum)] that TDP-43 is also deposited in the insular cortex, ventral striatum, basal forebrain, substantia nigra, midbrain tectum, and the inferior olive of the medulla oblongata, in Alzheimer's disease. The conditional probability analysis produced six significantly different stages (P < 0.01), and suggests that TDP-43 deposition begins in the amygdala (stage 1), then moves to entorhinal cortex and subiculum (stage 2); to the dentate gyrus of the hippocampus and occipitotemporal cortex (stage 3); insular cortex, ventral striatum, basal forebrain and inferior temporal cortex (stage 4); substantia nigra, inferior olive and midbrain tectum (stage 5); and finally to basal ganglia and middle frontal cortex (stage 6). This updated staging scheme is superior to our previous staging scheme, classifying 100% of the cases (versus 94% in the old scheme), based on criteria provided, and shows clinical significance with some regions and with increasing stage. We discuss the relevance of the updated staging scheme, as well as its impact on the prion-like hypothesis of protein spread in neurodegenerative disease. We also address the issue of whether frontotemporal lobar degeneration with TDP-43 could be the primary pathology in stage 6.
在本研究中，我们通过评估193例阿尔茨海默病患者14个不同脑区（8个先前描述的脑区加上6个新报告的脑区）中TDP-43的分布情况，更新了阿尔茨海默病分期方案中的TDP-43，并使用条件概率来模拟TDP-43在这14个脑区中的扩散。我们发现，除了我们先前报告的8个原始区域[杏仁核、内嗅皮质、海马旁回、海马齿状回、枕颞叶皮质、颞下回、额中回和基底神经节（壳核/苍白球）]外，在阿尔茨海默病中，TDP-43还沉积于岛叶皮质、腹侧纹状体、基底前脑、黑质、中脑顶盖和延髓下橄榄核。条件概率分析产生了6个显著不同的阶段（P < 0.01），表明TDP-43沉积始于杏仁核（第1阶段），然后转移至内嗅皮质和海马旁回（第2阶段）；至海马齿状回和枕颞叶皮质（第3阶段）；岛叶皮质、腹侧纹状体、基底前脑和颞下回（第4阶段）；黑质、下橄榄核和中脑顶盖（第5阶段）；最后至基底神经节和额中回（第6阶段）。这个更新后的分期方案优于我们之前的分期方案，根据所提供的标准，能对100%的病例进行分类（旧方案为94%），并且在一些区域以及随着分期增加显示出临床意义。我们讨论了更新后的分期方案的相关性，以及它对神经退行性疾病中蛋白质传播的朊病毒样假说的影响。我们还探讨了TDP-43阳性的额颞叶痴呆是否可能是第6阶段的主要病理改变这一问题。
