Penn Frontotemporal Degeneration Center, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
Digital Neuropathology Laboratory, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
Ann Neurol. 2019 May;85(5):630-643. doi: 10.1002/ana.25465. Epub 2019 Mar 28.
To measure postmortem burden of frontotemporal lobar degeneration (FTLD) with TDP-43 (FTLD-TDP) or tau (FTLD-Tau) proteinopathy across hemispheres in primary progressive aphasia (PPA) using digital histopathology and to identify clinicopathological correlates of these distinct proteinopathies.
In an autopsy cohort of PPA (FTLD-TDP = 13, FTLD-Tau = 14), we analyzed laterality and regional distribution of postmortem pathology, quantified using a validated digital histopathological approach, in available brain tissue from up to 8 cortical regions bilaterally. We related digital pathology to antemortem structural neuroimaging and specific clinical language features.
Postmortem cortical pathology was left-lateralized in both FTLD-TDP (beta = -0.15, standard error [SE] = 0.05, p = 0.007) and FTLD-Tau (beta = -0.09, SE = 0.04, p = 0.015), but the degree of lateralization decreased with greater overall dementia severity before death (beta = -8.18, SE = 3.22, p = 0.015). Among 5 core pathology regions sampled, we found greatest pathology in left orbitofrontal cortex (OFC) in FTLD-TDP, which was greater than in FTLD-Tau (F = 47.07, df = 1,17, p < 0.001), and in left midfrontal cortex (MFC) in FTLD-Tau, which was greater than in FTLD-TDP (F = 19.34, df = 1,16, p < 0.001). Postmortem pathology was inversely associated with antemortem magnetic resonance imaging cortical thickness (beta = -0.04, SE = 0.01, p = 0.007) in regions matching autopsy sampling. Irrespective of PPA syndromic variant, single-word comprehension impairment was associated with greater left OFC pathology (t = -3.72, df = 10.72, p = 0.004) and nonfluent speech with greater left MFC pathology (t = -3.62, df = 12.00, p = 0.004) among the 5 core pathology regions.
In PPA, FTLD-TDP and FTLD-Tau have divergent anatomic distributions of left-lateralized postmortem pathology that relate to antemortem structural imaging and distinct language deficits. Although other brain regions may be implicated in neural networks supporting these complex language measures, our observations may eventually help to improve antemortem diagnosis of neuropathology in PPA. Ann Neurol 2019;85:630-643.
使用数字组织病理学方法，在原发性进行性失语症（PPA）中测量额颞叶变性（FTLD）的死后负担，伴 TDP-43（FTLD-TDP）或 tau（FTLD-Tau）蛋白病变，以鉴定这些不同蛋白病变的临床病理相关性。
在 PPA（FTLD-TDP=13，FTLD-Tau=14）的尸检队列中，我们分析了双侧多达 8 个皮质区的死后病理学的侧别和区域分布，使用经过验证的数字组织病理学方法进行定量。我们将数字病理学与生前结构神经影像学和特定的临床语言特征联系起来。
FTLD-TDP（β=-0.15，标准误差[SE]=0.05，p=0.007）和 FTLD-Tau（β=-0.09，SE=0.04，p=0.015）的死后皮质病理学呈左侧偏侧化，但随着死亡前总体痴呆严重程度的增加，侧化程度降低（β=-8.18，SE=3.22，p=0.015）。在 5 个取样的核心病理学区域中，我们发现 FTLD-TDP 中左侧眶额皮质（OFC）的病理学最大，大于 FTLD-Tau（F=47.07，df=1,17，p<0.001），而 FTLD-Tau 中左侧额中回（MFC）的病理学最大，大于 FTLD-TDP（F=19.34，df=1,16，p<0.001）。死后病理学与匹配尸检取样的磁共振成像皮质厚度呈负相关（β=-0.04，SE=0.01，p=0.007）。无论 PPA 综合征变异如何，单字理解障碍与左侧 OFC 病理学更大有关（t=-3.72，df=10.72，p=0.004），非流畅性言语与左侧 MFC 病理学更大有关（t=-3.62，df=12.00，p=0.004）在 5 个核心病理学区域中。
在 PPA 中，FTLD-TDP 和 FTLD-Tau 具有左侧偏侧化的死后病理学的不同解剖分布，与生前结构成像和不同的语言缺陷有关。尽管其他脑区可能与支持这些复杂语言测量的神经网络有关，但我们的观察结果可能最终有助于改善 PPA 中神经病理学的生前诊断。
