背景：肌萎缩侧索硬化（amyotrophic lateral sclerosis, ALS）和额颞叶痴呆 （frontotemporal dementia, FTD）逐渐被认为属于同一谱系疾病。ALS-FTD 是一种罕见疾病，特别是中国。ALS-FTD预后较单纯的ALS或FTD更差。有研究发现认知障碍起病的 ALS-FTD（cognitive onset ALS-FTD, ALS-FTD-C）中位生存期要显著 长于运动障碍起病的患者（motor onset ALS-FTD, ALS-FTD-M），但两亚组间病理生理机制的差异尚不明确。目的：比较认知障碍起病与运动障碍起病 ALS-FTD 患者生存期、脑灰质结构、脑血流量及脑白质纤维的差异。方法：本研究纳入 2013 年 7 月至 2020 年 10 月北京协和医院诊断为 ALS-FTD 的 26例患者，进行基线临床信息采集、肌电图检查。定期电话随访，采集患者生存状态、改良版 ALS 功能评分（revised ALS functional rating scale，ALSFRS-R）等信息。采 用 Kaplan-Meier 生存分析比较 ALS-FTD-C 和 ALS-FTD-M 的中位生存期。7 例ALS-FTD-C、5 例 ALS-FTD-M 及 10 例年龄、性别、文化程度相匹配的健康对照者（healthy control, HC）完成磁共振扫描，采集受试者的 3D-T1W 脑结构像、3D-伪连续动脉自旋标记图像及弥散张量成像。应用基于体素的分析方法比较两亚组患者的脑灰质萎缩和低灌注，应用基于纤维束示踪的空间统计分析比较两亚组的脑白质纤维束损害。将影像学参数与临床指标进行相关性分析。结果：ALS-FTD-C 中位生存期长于 ALS-FTD-M，但未见统计学差异。ALS-FTD-C的运动中位生存期与 ALS-FTD-M 无显著性差异。脑分割结果显示，ALS-FTD 及ALS-FTD-C的相对全脑灰质体积、相对全脑白质体积均低于HC。脑灰质结构的比较显示，ALS-FTD 较 HC 存在双侧运动区、额颞叶、岛叶及前扣带回灰质体积减少。ALS-FTD-C 在上述区域存在广泛的灰质体积减少，相反，ALS-FTD-M 灰质体积减少的脑区则局限于右侧额下回、左侧颞叶和双侧岛叶。直接比较发现ALS-FTD-C 较 ALS-FTD-M 存在右侧颞中回、岛叶及角回灰质体积减少。脑血流量的比较显示，ALS-FTD 较 HC 存在双侧背外侧额上回的低灌注，ALS-FTD-C 的低灌注区还包括双侧颞叶、前额叶和前扣带回，未发现 ALS-FTD-M 与 HC 及ALS-FTD-C 与 ALS-FTD-M 的脑灌注差异。脑白质结构的比较显示，ALS-FTD 较HC 存在双侧皮质脊髓束、胼胝体辐射线枕部、放射冠及胼胝体等白质纤维受损。ALS-FTD-C 较 ALS-FTD-M 的脑白质纤维受累更广泛。ALS-FTD 患者的相关性分析显示，特定区域的灰质体积减少分别与ALSFRS-R、总病程及核磁年龄相关。结论：本队列 ALS-FTD-C 的中位生存期数值上长于 ALS-FTD-M，但未见统计学差异。ALS-FTD-C 出现运动障碍后的生存期与 ALS-FTD-M 相似，提示影响 ALS-FTD患者预后的主要因素可能是运动的受累而非认知损害。多模态影像学研究的结果发现 ALS-FTD-C 较 ALS-FTD-M 存在更广泛的脑灰质萎缩、低血流量及白质纤维束损害，初步揭示了两亚组患者上运动神经元和脑运动区外病理基础的差异。

Background：Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are increasingly considered part of the same incurable disease continuum. ALS-FTD is rare, especially in China. ALS-FTD exhibited worse prognosis than patients with pure ALS or FTD. Cognitive onset ALS-FTD (ALS-FTD-C) patients have shown significantly longer survival compared to motor onset (ALS-FTD-M) patients. However, the pathophysiological differences between these subgroups are still poorly understood. Objectives：This study aimed to compare clinical prognosis, gray matter structure, cerebral blood flow (CBF) and white matter changes between ALS-FTD-C and ALS-FTD-M. Methods：We enrolled 26 patients diagnosed as ALS-FTD in Peking Union Medical College Hospital from March 2013 to October 2020. Baseline clinical data were collected, and electromyography was performed and documented. Regular telephone follow-ups recorded survival status and the revised ALS functional rating scale (ALSFRS-R). Kaplan-Meier survival analysis was used to compare the median survival of ALS-FTD-C and ALS-FTD-M. Seven ALS-FTD-C, 5 ALS-FTD-M and 10 healthy controls (HC) with matching age, gender and education level completed the MRI scan. 3D-T1W brain structure imaging, 3D-pseudo continuous arterial spin labeled imaging and diffusion tensor imaging of all participants were collected. Gray matter volume (GMV) and CBF of ALS-FTD-C and ALS-FTD-M subgroups were compared using voxel-based analysis. White matter fibers of the two subgroups were compared using tract-based spatial statistics. Correlations between imaging parameters and clinical data were also analyzed. Results：ALS-FTD-C showed a longer median survival than ALS-FTD-M, which was not statistically significant. Median survival of motor symptoms was not different between two subgroups. The brain segmentation results displayed that in ALS-FTD patients and the ALS-FTD-C subgroup, the relative total volume of gray matter and the relative total volume of white matter were significantly lower than those in HC. In the comparison of gray matter structure, ALS-FTD patients had significant GMV reduction in bilateral precentral gyrus, frontotemporal lobe, insula, and anterior cingulate gyrus compared to HC. ALS-FTD-C showed more widespread GMV reduction in these areas while the GMV reduction of ALS-FTD-M was limited to the right inferior frontal gyrus, left temporal lobe, and bilateral insula. Further, direct comparison revealed ALS-FTD-C had significantly lower GMV in right middle temporal gyrus, insula, and angular gyrus than ALS-FTD-M. In the comparison of CBF, ALS-FTD patients presented significant hypoperfusion in bilateral dorsolateral superior frontal gyrus compared to HC. In ALS-FTD-C, hypoperfusion was also found in bilateral temporal lobe, prefrontal cortex and anterior cingulate gyrus. However, there were no significant perfusion differences between HC vs. ALS-FTD-M and ALS-FTD-C vs. ALS-FTD-M. In the comparison of white matter structure, ALS-FTD patients presented damage of white matter fibers in the bilateral corticospinal tract, forceps major, corona radiata, and corpus callosum compared with HC. ALS-FTD-C had more widespread damage of white matter fibers than ALS-FTD-M. Additionally, in ALS-FTD patients, ALSFRS-R scores, disease duration and age at MRI were correlated with GMV reduction in specific brain regions. Conclusions ： In this cohort, ALS-FTD-C had a longer median survival than ALS-FTD-M, which was not statistically significant. When ALS-FTD-C patients developed motor symptoms, their survival time was similar to ALS-FTD-M. These results indicated that motor involvement rather than cognitive deficits may be the defining factor in the survival of ALS-FTD. The imaging results displayed that ALS-FTD-C had more widespread cortical atrophy, hypoperfusion and damage of white matter fibers than ALS-FTD-M. Our study preliminarily revealed the pathological differences between these subgroups in upper motor neuron and brain extra-motor regions.