Redefining the multidimensional clinical phenotypes of frontotemporal lobar degeneration syndromes
Redefining the multidimensional clinical phenotypes of frontotemporal lobar degeneration syndromes
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DOI：
10.1093/brain/awaa097
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发表时间：
2020-05-01
期刊：
影响因子：
14.5
通讯作者：
Rowe, James B.
中科院分区：
文献类型：
--
作者：
Murley, Alexander G.;Coyle-Gilchrist, Ian;Rowe, James B.
额颞叶变性引起的综合征具有高度的异质性和重叠的临床特征。在过去的十年中，临床诊断标准的改进有了很大的进步，但我们认为，通过对临床表型和脑形态测量的跨诊断方法，可以更好地理解病因学、病理生理学和对症治疗。在一项横断面流行病学研究中，我们检查了310名可能由额颞叶变性引起的综合征患者，包括行为变异型额颞叶痴呆、不流利的原发性进行性失语症(PPA)、进行性核上性瘫痪和皮质-基底综合征的语义变异型。我们包括对数产后纤溶酶原激活物(PPA)患者和那些符合PPA诊断标准但不是特定亚型的患者。到目前为止，有49名患者被诊断为神经病理。主成分分析确定了症状维度，大致概括了主要临床症状的核心特征。然而，这些维度上的特定于受试者的分数在不同的诊断组之间显示出相当大的重叠。62%的参与者具有符合一种以上综合症诊断标准的表型特征。行为障碍在所有人群中普遍存在。44%的皮质-基底综合征患者有进行性核上性麻痹样特征，30%的进行性核上性瘫痪患者有皮质-基底综合征样特征。许多进行性核上性瘫痪和皮质-基底综合征患者的语言障碍与不流利的变异型PPA一致，而行为变异型额颞痴呆患者通常有语义障碍。对一组患者(n=133)进行了基于多变量来源的形态测量，我们确定了不同诊断组间存在的协变性脑萎缩模式。对临床和成像成分的典型相关分析发现了三个关键的大脑行为关系，在队列中具有连续的谱，而不是离散的诊断实体。在46例获得随访(平均3.6年)的患者中，症状重叠随着时间的延长而增加。综上所述，这些结果表明，与额颞叶变性相关的综合征并不是根据其临床特征或脑结构变化形成相互排斥的离散类别，而是存在于多维光谱中。患者往往表现出多种疾病的诊断特征，而行为、运动和语言领域的缺陷并不局限于特定的诊断群体。认识到临床表型的个体差异对于临床治疗和了解发病机制都很重要。我们认为，额颞叶变性综合征频谱的跨诊断方法提供了一个有用的框架，可以用来了解疾病的病因、进展和异质性，并针对更高比例的患者进行未来的治疗。
The syndromes caused by frontotemporal lobar degeneration have highly heterogeneous and overlapping clinical features. There has been great progress in the refinement of clinical diagnostic criteria in the past decade, but we propose that a better understanding of aetiology, pathophysiology and symptomatic treatments can arise from a transdiagnostic approach to clinical phenotype and brain morphometry. In a cross-sectional epidemiological study, we examined 310 patients with a syndrome likely to be caused by frontotemporal lobar degeneration, including behavioural variant frontotemporal dementia, non-fluent, and semantic variants of primary progressive aphasia (PPA), progressive supranuclear palsy and corticobasal syndrome. We included patients with logopenic PPA and those who met criteria for PPA but not a specific subtype. To date, 49 patients have a neuropathological diagnosis. A principal component analysis identified symptom dimensions that broadly recapitulated the core features of the main clinical syndromes. However, the subject-specific scores on these dimensions showed considerable overlap across the diagnostic groups. Sixty-two per cent of participants had phenotypic features that met the diagnostic criteria for more than one syndrome. Behavioural disturbance was prevalent in all groups. Forty-four per cent of patients with corticobasal syndrome had progressive supranuclear palsy-like features and 30% of patients with progressive supranuclear palsy had corticobasal syndrome-like features. Many patients with progressive supranuclear palsy and corticobasal syndrome had language impairments consistent with non-fluent variant PPA while patients with behavioural variant frontotemporal dementia often had semantic impairments. Using multivariate source-based morphometry on a subset of patients (n = 133), we identified patterns of covarying brain atrophy that were represented across the diagnostic groups. Canonical correlation analysis of clinical and imaging components found three key brain-behaviour relationships, with a continuous spectrum across the cohort rather than discrete diagnostic entities. In the 46 patients with follow-up (mean 3.6 years) syndromic overlap increased with time. Together, these results show that syndromes associated with frontotemporal lobar degeneration do not form discrete mutually exclusive categories from their clinical features or structural brain changes, but instead exist in a multidimensional spectrum. Patients often manifest diagnostic features of multiple disorders while deficits in behaviour, movement and language domains are not confined to specific diagnostic groups. It is important to recognize individual differences in clinical phenotype, both for clinical management and to understand pathogenic mechanisms. We suggest that a transdiagnostic approach to the spectrum of frontotemporal lobar degeneration syndromes provides a useful framework with which to understand disease aetiology, progression, and heterogeneity and to target future treatments to a higher proportion of patients.