Antemortem behavioural and anatomic abnormalities have largely been associated with right hemisphere disease in behavioural-variant frontotemporal dementia, but post-mortem neuropathological examination of bilateral hemispheres remains to be defined. Here we measured the severity of post-mortem pathology in both grey and white matter using a validated digital image analysis method in four cortical regions sampled from each hemisphere in 26 patients with behavioural-variant frontotemporal dementia, including those with frontotemporal degeneration (i.e. tau = 9, TDP-43 = 14, or FUS = 1 proteinopathy) or Alzheimer’s pathology (n = 2). We calculated an asymmetry index based on the difference in measured pathology from each left-right sample pair. Analysis of the absolute value of the asymmetry index (i.e. degree of asymmetry independent of direction) revealed asymmetric pathology for both grey and white matter in all four regions sampled in frontototemporal degeneration patients with tau or TDP-43 pathology (P ≤ 0.01). Direct interhemispheric comparisons of regional pathology measurements within-subjects in the combined tauopathy and TDP-43 proteinopathy group found higher pathology in the right orbitofrontal grey matter compared to the left (P < 0.01) and increased pathology in ventrolateral temporal lobe grey matter of the left hemisphere compared to the right (P < 0.02). Preliminary group-wise comparisons between tauopathy and TDP-43 proteinopathy groups found differences in patterns of interhemispheric burden of grey and white matter regional pathology, with greater relative white matter pathology in tauopathies. To test the association of pathology measurement with ante-mortem observations, we performed exploratory analyses in the subset of patients with imaging data (n = 15) and found a direct association for increasing pathologic burden with decreasing cortical thickness in frontotemporal regions on ante-mortem imaging in tauopathy (P = 0.001) and a trend for TDP-43 proteinopathy (P = 0.06). Exploratory clinicopathological correlations demonstrated an association of socially-inappropriate behaviours with asymmetric right orbitofrontal grey matter pathology, and reduced semantically-guided category naming fluency was associated asymmetric white matter pathology in the left ventrolateral temporal region. We conclude that pathologic disease burden is distributed asymmetrically in behavioural-variant frontotemporal dementia, although not universally in the right hemisphere, and this asymmetry contributes to the clinical heterogeneity of the disorder. The basis for this asymmetric profile is enigmatic but may reflect distinct species or strains of tau and TDP-43 pathologies with propensities to spread by distinct cell- and region-specific mechanisms. Patterns of region-specific pathology in the right hemisphere as well as the left hemisphere may play a role in antemortem clinical observations, and these observations may contribute to antemortem identification of molecular pathology in frontotemporal degeneration.

中文翻译：

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行为变异额颞叶痴呆的验尸后神经病理学的不对称性

行为变异性额颞痴呆的前半身行为和解剖异常很大程度上与右半球疾病有关，但是对双侧半球的死后神经病理学检查仍有待确定。在这里，我们使用经过验证的数字图像分析方法，对26名行为变异型额颞痴呆患者，包括额颞变性患者（即tau = 9，TDP-43 = 14或FUS = 1蛋白病）或阿尔茨海默氏病（n= 2）。我们根据每个左右样本对的测量病理学差异计算了不对称指数。不对称指数（即不对称性与方向无关的程度）的绝对值的分析在frontototemporal变性患者与tau蛋白或TDP-43病理（采样所有四个区域显示非对称病理两种灰质和白质P ≤0.01）。在tauopathy和TDP-43蛋白病联合治疗组的受试者内部进行的区域内病理学测量的直接半球间比较发现，右侧眶额灰质的病理学高于左侧（P <0.01），左侧腹侧颞叶灰质的病理学增加与右半球相比（P<0.02）。牛磺酸病和TDP-43蛋白病各组之间的初步分组比较发现，灰白质区域病理的半球间负担模式有所不同，而牛卵白质病的相对白质病理更大。为了检验病理学测量与验尸观察的关联，我们对具有成像数据（n = 15）的患者亚组进行了探索性分析，发现在验尸前额颞区，病理负担增加与皮质厚度减少直接相关tauopathy中的影像学表现（P = 0.001）和TDP-43蛋白病的趋势（P= 0.06）。探索性的临床病理相关性表明，社交不当行为与不对称的右眶额灰质病理相关，并且语义引导的类别命名流畅性降低与左腹外侧颞区的不对称白质病理相关。我们得出的结论是，病理行为负担在行为变异性额颞痴呆中不对称分布，尽管在右半球并不普遍分布，并且这种不对称性导致该疾病的临床异质性。这种不对称分布的基础是神秘的，但可能反映出tau和TDP-43病理学的不同物种或菌株，并倾向于通过不同的细胞和区域特异性机制传播。